Monod-Wyman-Changeux Research Articles

De novo design of allosterically switchable protein assemblies

Allosteric modulation of protein function, wherein the binding of an effector to a protein triggers conformational changes at distant functional sites, plays a central part in the control of metabolism and cell signalling1–3. There has been considerable interest in designing allosteric systems, both to gain insight into the mechanisms underlying such ‘action at a distance’ modulation and to create synthetic proteins whose functions can be regulated by effectors4–7. However, emulating the subtle conformational changes distributed across many residues, characteristic of natural allosteric proteins, is a significant challenge8,9. Here, inspired by the classic Monod–Wyman–Changeux model of cooperativity10, we investigate the de novo design of allostery through rigid-body coupling of peptide-switchable hinge modules11 to protein interfaces12 that direct the formation of alternative oligomeric states. We find that this approach can be used to generate a wide variety of allosterically switchable systems, including cyclic rings that incorporate or eject subunits in response to peptide binding and dihedral cages that undergo effector-induced disassembly. Size-exclusion chromatography, mass photometry13 and electron microscopy reveal that these designed allosteric protein assemblies closely resemble the design models in both the presence and absence of peptide effectors and can have ligand-binding cooperativity comparable to classic natural systems such as haemoglobin14. Our results indicate that allostery can arise from global coupling of the energetics of protein substructures without optimized side-chain–side-chain allosteric communication pathways and provide a roadmap for generating allosterically triggerable delivery systems, protein nanomachines and cellular feedback control circuitry.

Is allostery a fuzzy concept?

Allostery is an important property of biological macromolecules which regulates diverse biological functions such as catalysis, signal transduction, transport, and molecular recognition. However, the concept was expressed using two different definitions by J. Monod and, over time, more have been added by different authors, making it fuzzy. Here, we reviewed the different meanings of allostery in the current literature and found that it has been used to indicate that the function of a protein is regulated by heterotropic ligands, and/or that the binding of ligands and substrates presents homotropic positive or negative cooperativity, whatever the hypothesized or demonstrated reaction mechanism might be. Thus, proteins defined to be allosteric include not only those that obey the two-state concerted model, but also those that obey different reaction mechanisms such as ligand-induced fit, possibly coupled to sequential structure changes, and ligand-linked dissociation-association. Since each reaction mechanism requires its own mathematical description and is defined by it, there are many possible 'allosteries'. This lack of clarity is made even fuzzier by the fact that the reaction mechanism is often assigned imprecisely and/or implicitly in the absence of the necessary experimental evidence. In this review, we examine a list of proteins that have been defined to be allosteric and attempt to assign a reaction mechanism to as many as possible.

What can European security architecture look like in the wake of Russia’s war on Ukraine?

ABSTRACT The paper outlines the most likely scenarios of the future European security architecture based on an analysis of several drivers, such as Russia’s leadership’s perception of Ukraine, the mindset of the Putinist elite, Russia’s state geopolitics, the domestic situation and prospects of a regime change in Russia, economic sanctions against Russia, energy and the export of Russia’s energy resources, and the positions of key Euratlantic actors. The current “unstable balance model” will remain the most likely scenario in case of a conservation of the situation on the Ukrainian battlefields. Since the concert model of security architecture entails a lack of a revisionist agenda among all the actors, the only reasonably probable security management upgrade is a “positive stable balance”. This scenario is conditioned on degrading Russia’s military capacity, Ukraine’s military advancements on the battlefields, a weakening of the Russian economy and maintaining the support for Ukraine in the EU and NATO.

How much does TRPV1 deviate from an ideal MWC-type protein?

Many ion channels are known to behave as an allosteric protein, coupling environmental stimuli captured by specialized sensing domains to the opening of a central pore. The classic Monod-Wyman-Changeux (MWC) model, originally proposed to describe binding of gas molecules to hemoglobin, has been widely used as a framework for analyzing ion channel gating. Here, we address the issue of how accurately the MWC model predicts activation of the capsaicin receptor TRPV1 by vanilloids. Taking advantage of a concatemeric design that makes it possible to lock TRPV1 in states with zero to four bound vanilloid molecules, we showed quantitatively that the overall gating behavior is satisfactorily predicted by the MWC model. There is, however, a small yet detectable subunit position effect: ligand binding to two kitty-corner subunits is 0.3–0.4 kcal/mol more effective in inducing opening than binding to two neighbor subunits. This difference—less than 10% of the overall energetic contribution from ligand binding—might be due to the restriction on subunit arrangement imposed by the planar membrane; if this is the case, then the position effect is not expected in hemoglobin, in which each subunit is related equivalently to all the other subunits.

A novel role for phospholamban in the thalamic reticular nucleus

The thalamic reticular nucleus (TRN) is a brain region that influences vital neurobehavioral processes, including executive functioning and the generation of sleep rhythms. TRN dysfunction underlies hyperactivity, attention deficits, and sleep disturbances observed across various neurodevelopmental disorders. A specialized sarco-endoplasmic reticulum calcium (Ca2+) ATPase 2 (SERCA2)-dependent Ca2+ signaling network operates in the dendrites of TRN neurons to regulate their bursting activity. Phospholamban (PLN) is a prominent regulator of SERCA2 with an established role in myocardial Ca2+-cycling. Our findings suggest that the role of PLN extends beyond the cardiovascular system to impact brain function. Specifically, we found PLN to be expressed in TRN neurons of the adult mouse brain, and utilized global constitutive and innovative conditional genetic knockout mouse models in concert with electroencephalography (EEG)-based somnography and the 5-choice serial reaction time task (5-CSRTT) to investigate the role of PLN in sleep and executive functioning, two complex behaviors that map onto thalamic reticular circuits. The results of the present study indicate that perturbed PLN function in the TRN results in aberrant TRN-dependent phenotypes in mice (i.e., hyperactivity, impulsivity and sleep deficits) and support a novel role for PLN as a critical regulator of SERCA2 in the TRN neurocircuitry.

A three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D

Modulation of protein function through allosteric regulation is central in biology, but biomacromolecular systems involving multiple subunits and ligands may exhibit complex regulatory mechanisms at different levels, which remain poorly understood. Here, we discover an aldo-keto reductase termed AKRtyl and present its three-level regulatory mechanism. Specifically, by combining steady-state and transient kinetics, X-ray crystallography and molecular dynamics simulation, we demonstrate that AKRtyl exhibits a positive synergy mediated by an unusual Monod-Wyman-Changeux (MWC) paradigm of allosteric regulation at low concentrations of the cofactor NADPH, but an inhibitory effect at high concentrations is observed. While the substrate tylosin binds at a remote allosteric site with positive cooperativity. We further reveal that these regulatory mechanisms are conserved in AKR12D subfamily, and that substrate cooperativity is common in AKRs across three kingdoms of life. This work provides an intriguing example for understanding complex allosteric regulatory networks.

Symmetry of a partially-ligated state maintained by dynamics in a negatively cooperative system

Symmetry was a key concept underlying the MWC model for allostery advanced in 1965 by Monod, Wyman, and Changeux. The reciprocal interactions of symmetrically-arranged identical subunits were proposed to stabilize multimeric assemblies together with the free energy from bound ligands that progressively favor a monomer-like state. Structural symmetry of subunits was assumed to be maintained in the partially-ligated states, even if ligand placement itself is not symmetric. Partially-ligated states can be populated sufficiently for experimental study only in negatively cooperative systems, which were not considered in the MWC model. The work reported here uses 1H, 13C, 15N, and 19F NMR to evaluate the structural symmetry of the hexameric arginine repressor of E. coli, a negatively cooperative system, with a single bound L-arginine ligand. The analysis indicates that the singly-ligated hexamer maintains structural symmetry as probed by these four NMR nuclei. The results are consistent with earlier molecular dynamics simulations suggesting that the global dynamics of the singly-ligated assembly are harnessed to maintain structural symmetry. The results extend MWC symmetry concepts to this negatively cooperative system, and indicate a role for global dynamics in allostery.

The dual role of outflows in quenching satellites of low-mass hosts: NGC 3109

ABSTRACT While dwarf galaxies observed in the field are overwhelmingly star forming, dwarf galaxies in environments as dense or denser than the Milky Way are overwhelmingly quenched. In this paper, we explore quenching in the lower density environment of the Small-Magellanic-Cloud-mass galaxy NGC 3109 (M$_* \sim 10^8 \, \text{M}_\odot$), which hosts two known dwarf satellite galaxies (Antlia and Antlia B), both of which are ${\rm H}\, \rm{\small I}$ deficient compared to similar galaxies in the field and have recently stopped forming stars. Using a new semi-analytic model in concert with the measured star formation histories and gas masses of the two dwarf satellite galaxies, we show that they could not have been quenched solely by direct ram pressure stripping of their interstellar media, as is common in denser environments. Instead, we find that separation of the satellites from pristine gas inflows, coupled with stellar-feedback-driven outflows from the satellites (jointly referred to as the starvation quenching model), can quench the satellites on time-scales consistent with their likely infall times into NGC 3109’s halo. It is currently believed that starvation is caused by ‘weak’ ram pressure that prevents low-density, weakly bound gas from being accreted on to the dwarf satellite, but cannot directly remove the denser interstellar medium. This suggests that star-formation-driven outflows serve two purposes in quenching satellites in low-mass environments: outflows from the host form a low-density circumgalactic medium that cannot directly strip the interstellar media from its satellites, but is sufficient to remove loosely bound gaseous outflows from the dwarf satellites driven by their own star formation.

A sensory-friendly adaptive concert model supported by caregiver perspectives

Attending a concert may prove difficult for individuals with exceptionalities or disabilities and those who support them. While traditional performance environments may not feel welcoming or amenable for individuals with exceptionalities and their families, arts organizations have recently made efforts to produce concerts that address barriers to accessibility. These adaptive concerts, most frequently labeled as Sensory-Friendly Concerts, attempt to create environments suitable for diverse communities, supporting individuals and groups who are frequently underrepresented as audience members in performance contexts. This article explores adaptive music performances, contributing a model for sensory-friendly adaptive concerts supported by caregivers’ perspectives through a post-concert survey. The model proposed includes four areas of adaptation: pre-show work, environment audit, extra-musical aids, and programming adjustments. The authors outline the various modifications with data points from a sample of adaptive concert caregiver attendees ( n = 15), aligning the theoretical model with practice to provide practical examples and tangible outputs for researchers, presenters, musicians, educators, and policymakers.

Double concertos for violin and cello with orchestra by Johannes Brahms and Vitalyi Kyreiko: genrе and style dimentions

The relevance of the article. The Concertos for violin and cello with symphony orchestra by J. Brahms (a moll, op. 102) and V. Kyreikо (a moll, op. 65) are considered in terms of embodying the artistic pursuit of composers of different eras and national schools. Genre-stylistic features are outlined, their individual and common features are revealed, which testify to the preservation and development of the tradition of the concert genre, the reinterpretation of the Brahms concert model in a new cultural context. It is emphasized that works belong to the type of symphonized concert, in which the means of symphonic transformation of thematic material, a rich polyphonic texture, complex forms of interaction between soloists and orchestra prevail. It is noted that the methods of symphonizing the musical fabric take place in accordance with the creative attitude of each composer, whose common stylistic space fits into the paradigm of romanticism — neoromanticism. Special attention paid to the V. Kyreiko’s concerto for violine and cello with orchestra, as the first in Ukraine double concert for string instruments, which is considered from point of imitation and development of the genre of instrumental concert. Emphasized the uniqueness of the author’s concept, which is revealed in the combination of deep musical content and clear form, understanding of the expressive possibilities of the violin and cello, and the disclosure of the natural beauty of the sound of the instruments.
 The main objective of the article is to compare the genre-stylistic features of the double concertos for violin and cello with the orchestra by J. Brahms and V. Kyreiko and to reveal the possibilities of their modern performance interpretation.
 The methodology of the research methodology includes the following methods: historical, which made it possible to determine the historical framework and attribute the work of composers to a certain era and style; genre-style analysis, which made it possible to reveal the stylistic features of musical expressiveness in the specified works of the composers; comparative analysis, thanks to which it became possible to compare intonation genre-style complexes in the work of composers; performance analysis, with the help of which the artistic and performance specifics of the double concerto for violin and cello with orchestra are highlighted in the aspect of updating the genre tradition of the 19th - second half of the 20th centuries.
 Results and conclusions. A comparative analysis of two original in design and methods of musical implementation of concertos for violin and cello and symphony orchestra by J. Brahms and V. Kуreiko allowed us to outline the wide genre and style space of existence of these bright artistic phenomena, which extends from the romanticism of the 19th century to the neo-romanticism of the 20th century, demonstrates the durability genre tradition, reveals the common features and individual differences of these works. Despite the different national and cultural context, both works embody the symphonic scale of the development of musical thought, they are marked by the breadth and ambiguity of lyrical and dramatic images. The thematic layer of the concerts is distinguished by its imaginative breadth: an epic story, elegiac romantic-song episodes, a multifaceted lyricaldramatic sphere, genre-dance finales with different emotional moods. The principle of thematic development is built on the basis of complementarity, contrasting juxtapositions of theme-images, avoidance of sharp clashes, associatively reminiscent of romantic poetic dramatic concepts. The double concertos for violin and cello by J. Brahms and V. Kуreiko demonstrate perfect skill in the presentation of each of the soloists, the construction of ensemble dialogues, and the interaction of the soloists with the orchestra. As a general trend, we state that both concerts continue the tradition of symphonizing the genre. Reviews of concerts performed by leading Ukrainian musicians of different generations (O. Horokhov — V. Chervov, B. Pivnenko — K. Polyanska) provide examples of standard performance versions, the performers' deep understanding of the composer's concepts, their inclusion in the general cultural and historical process. Undoubtedly, they are guidelines for further revealing the artistic potential of concerts.

The Farmer: A Reproducible Profile-fitting Photometry Package for Deep Galaxy Surveys

Abstract While space-borne optical and near-infrared facilities have succeeded in delivering a precise and spatially resolved picture of our Universe, their small survey area is known to underrepresent the true diversity of galaxy populations. Ground-based surveys have reached comparable depths but at lower spatial resolution, resulting in source confusion that hampers accurate photometry extractions. What once was limited to the infrared regime has now begun to challenge ground-based ultradeep surveys, affecting detection and photometry alike. Failing to address these challenges will mean forfeiting a representative view into the distant Universe. We introduce The Farmer: an automated, reproducible profile-fitting photometry package that pairs a library of smooth parametric models from The Tractor with a decision tree that determines the best-fit model in concert with neighboring sources. Photometry is measured by fitting the models on other bands leaving brightness free to vary. The resulting photometric measurements are naturally total, and no aperture corrections are required. Supporting diagnostics (e.g., χ 2) enable measurement validation. As fitting models is relatively time intensive, The Farmer is built with high-performance computing routines. We benchmark The Farmer on a set of realistic COSMOS-like images and find accurate photometry, number counts, and galaxy shapes. The Farmer is already being utilized to produce catalogs for several large-area deep extragalactic surveys where it has been shown to tackle some of the most challenging optical and near-infrared data available, with the promise of extending to other ultradeep surveys expected in the near future. The Farmer is available to download from GitHub (https://github.com/astroweaver/the_farmer) and Zenodo (https://doi.org/10.5281/zenodo.8205817).

The Queen of the Violin

The commercialized nineteenth century lyceum circuit provided the vehicle for Camilla Urso (1840-1902) to become America's first celebrity female violinist. Vizualizing six seasons between 1873-83 where Urso toured under lyceum bureau management in digital maps of my own creation, I argue industrialized transportation networks combined with the commercialized advertising and publicity of the lyceum circuit created a popular concert model that expanded Urso's audience and raised her concert fees. Urso's time on the lyceum circuit laid the foundation for her transnational career. Urso was never solely a lyceum musician, though exploring the role of lyceums and their bureaus in her career plays a key role in determining how she rose to fame and became America's most celebrated female violinist. Futhermore, Urso's lyceum career argues for classical music as a rural and commercial phenomenon of American popular culture in the nineteenth century.

Insight into influence of thermal radiation and Cattaneo–Christov model on ternary hybrid nanofluid (TiO2–Al2O3–MoS2/kerosene oil) and hybrid nanofluid (TiO2–Al2O3/kerosene oil) flow and heat transfer over a stretching sheet

The present research reports the impact of the Cattaneo–Christov (C-C) model and thermal radiation in concert with the suction/injection on boundary conditions on TiO2–Al2O3–MoS2/Kerosene oil ternary hybrid nanofluid (THNF) over a stretching sheet. The authors have also done a comparative analysis of the heat and mass transfer rate of ternary hybrid nanofluid and TiO2–Al2O3/Kerosene oil hybrid nanofluid flow. The code validation is done with a published study as a special case to validate the numerical code used to derive the numerical results of the present flow model. The flow equations are altered into ODEs with the help of similarity transformation, which are solved in MATLAB by the “bvp4c technique.” The graphs are drawn w.r.t. various parameters: heat source/sink, radiation, chemical reaction, suction/injection, thermal relaxation, and magnetic parameter. The influence of the aforementioned parameters on the velocity profile, thermal profile, concentration profile, heat, and mass transfer profile is displayed by graphs and tabular values. The heat and mass transfer rate enhance by elevating the value of the heat source/sink and radiation parameter. On boosting the magnitude of injection at the surface, the rate of mass transfer elevates. The results of this study can be used in various applications including drainage issues, chemical engineering, solar panels, solar absorption and filtration, ground stream hydrology, solar cells, and others, where flow over a sheet illustrates its significance and applicability.

Size limits the sensitivity of kinetic schemes

Living things benefit from exquisite molecular sensitivity in many of their key processes, including DNA replication, transcription and translation, chemical sensing, and morphogenesis. At thermodynamic equilibrium, the basic biophysical mechanism for sensitivity is cooperative binding, for which it can be shown that the Hill coefficient, a sensitivity measure, cannot exceed the number of binding sites. Generalizing this fact, we find that for any kinetic scheme, at or away from thermodynamic equilibrium, a very simple structural quantity, the size of the support of a perturbation, always limits the effective Hill coefficient. We show how this bound sheds light on and unifies diverse sensitivity mechanisms, including kinetic proofreading and a nonequilibrium Monod-Wyman-Changeux (MWC) model proposed for the E. coli flagellar motor switch, representing in each case a simple, precise bridge between experimental observations and the models we write down. In pursuit of mechanisms that saturate the support bound, we find a nonequilibrium binding mechanism, nested hysteresis, with sensitivity exponential in the number of binding sites, with implications for our understanding of models of gene regulation and the function of biomolecular condensates.

Spatial variability and temporal changes of POPs in European background air

Concentration data on POPs in air is necessary to assess the effectiveness of international regulations aiming to reduce the emissions of persistent organic pollutants (POPs) into the environment. POPs in European background air are continuously monitored using active- and passive air sampling techniques at a limited number of atmospheric monitoring stations. As a result of the low spatial resolution of such continuous monitoring, there is limited understanding of the main sources controlling the atmospheric burdens of POPs across Europe. The key objectives of this study were to measure the spatial and temporal variability of concentrations of POPs in background air with a high spatial resolution (n = 101) across 33 countries within Europe, and to use observations and models in concert to assess if the measured concentrations are mainly governed by secondary emissions or continuing primary emissions. Hexachlorobenzene (HCB) was not only the POP detected in highest concentrations (median: 67 pg/m3), but also the only POP that had significantly increased over the last decade. HCB was also the only POP that was positively correlated to latitude. For the other targeted POPs, the highest concentrations were observed in the southern part of Europe, and a declining temporal trend was observed. Spatial differences in temporal changes were observed. For example, γ-HCH (hexachlorocyclohexane) had the largest decrease in the south of Europe, while α-HCH had declined the most in central-east Europe. High occurrence of degradation products of the organochlorine pesticides and isomeric ratios indicated past usage. Model predictions of PCB-153 (2,2’,4,4’,5,5’-hexachlorobiphenyl) by the Global EMEP Multi-media Modelling System suggest that secondary emissions are more important than primary emissions in controlling atmospheric burdens, and that the relative importance of primary emissions are more influential in southern Europe compared to northern Europe. Our study highlights the major advantages of combining high spatial resolution observations with mechanistic modelling approaches to provide insights on the relative importance of primary- and secondary emission sources in Europe. Such knowledge is considered vital for policy makers aiming to assess the potential for further emission reduction strategies of legacy POPs.

The cold regions hydrological modelling platform for hydrological diagnosis and prediction based on process understanding

Cold regions involve hydrological processes that are not often addressed appropriately in hydrological models. The Cold Regions Hydrological Modelling platform (CRHM) was initially developed in 1998 to assemble and explore the hydrological understanding developed from a series of research basins spanning Canada and international cold regions. Hydrological processes and basin response in cold regions are simulated in a flexible, modular, object-oriented, multiphysics platform. The CRHM platform allows for multiple representations of forcing data interpolation and extrapolation, hydrological model spatial and physical process structures, and parameter values. It is well suited for model falsification, algorithm intercomparison and benchmarking, and has been deployed for basin hydrology diagnosis, prediction, land use change and water quality analysis, climate impact analysis and flood forecasting around the world. This paper describes CRHM’s capabilities, and the insights derived by applying the model in concert with process hydrology research and using the combined information and understanding from research basins to predict hydrological variables, diagnose hydrological change and determine the appropriateness of model structure and parameterisations.

Structural Basis of Sequential and Concerted Cooperativity.

Allostery is a property of biological macromolecules featuring cooperative ligand binding and regulation of ligand affinity by effectors. The definition was introduced by Monod and Jacob in 1963, and formally developed as the "concerted model" by Monod, Wyman, and Changeux in 1965. Since its inception, this model of cooperativity was seen as distinct from and not reducible to the "sequential model" originally formulated by Pauling in 1935, which was developed further by Koshland, Nemethy, and Filmer in 1966. However, it is difficult to decide which model is more appropriate from equilibrium or kinetics measurements alone. In this paper, we examine several cooperative proteins whose functional behavior, whether sequential or concerted, is established, and offer a combined approach based on functional and structural analysis. We find that isologous, mostly helical interfaces are common in cooperative proteins regardless of their mechanism. On the other hand, the relative contribution of tertiary and quaternary structural changes, as well as the asymmetry in the liganded state, may help distinguish between the two mechanisms.

Tip Speed Ratio Optimization: More Energy Production with Reduced Rotor Speed

A wind turbine’s tip speed ratio (TSR) is the linear speed of the blade’s tip, normalized by the incoming wind speed. For a given blade profile, there is a TSR that maximizes the turbine’s efficiency. The industry’s current practice is to impose the same TSR that maximizes the efficiency of a single, isolated wind turbine on every turbine of a wind farm. This article proves that this strategy is wrong. The article demonstrates that in every wind direction, there is always a subset of turbines that needs to operate at non-efficient conditions to provide more energy to some of their downstream counterparts to boost the farm’s overall production. The aerodynamic interactions between the turbines cause this. The authors employed the well-known Jensen wake model in concert with Particle Swarm Optimization to demonstrate the effectiveness of this strategy at Lillgrund, a wind farm in Sweden. The model’s formulation and implementation were validated using large-eddy simulation results. The AEP of Lillgrund increased by approximately 4% by optimizing and actively controlling the TSR. This strategy also decreased the farm’s overall TSR, defined as the average TSR of the turbines, by 8%, leading to several structural and environmental benefits. Note that both these values are farm-dependent and change from one farm to another; hence, this research serves as a proof of concept.

Concerted Model of Healthcare for Awá Indigenous of Nariño, Colombia.

Indigenous communities in Colombia are facing a critical health situation; alternative health care models based on the vision of the communities themselves are needed. The objective of this research was to create a health care model that decreases health inequities for the Indigenous Awá population of Nariño, Colombia. This study was guided by the paradigm of community-based participatory action research; the process was carried out in 2015 and 2016. The proposed Intercultural Health Care Model is essentially based on health promotion, disease prevention, community empowerment, social participation in health, decentralized health care and coordination between the two medicines (traditional and allopathic). Strategies such as those reported herein, with concerted efforts rather than imposition, maintain human rights and respect for the sovereignty and autonomy of Indigenous people.

Structural basis of retinal membrane guanylate cyclase regulation by GCAP1 and RD3.

Retinal membrane guanylate cyclases (RetGC1 and RetGC2) are expressed in photoreceptor rod and cone cells, where they promote the onset of visual recovery during phototransduction. The catalytic activity of RetGCs is regulated by their binding to regulatory proteins, guanylate cyclase activating proteins (GCAP1-5) and the retinal degeneration 3 protein (RD3). RetGC1 is activated by its binding to Ca2+-free/Mg2+-bound GCAP1 at low cytosolic Ca2+ levels in light-activated photoreceptors. By contrast, RetGC1 is inactivated by its binding to Ca2+-bound GCAP1 and/or RD3 at elevated Ca2+ levels in dark-adapted photoreceptors. The Ca2+ sensitive cyclase activation helps to replenish the cytosolic cGMP levels in photoreceptors during visual recovery. Mutations in RetGC1, GCAP1 or RD3 that disable the Ca2+-dependent regulation of cyclase activity are genetically linked to rod/cone dystrophies and other inherited forms of blindness. Here I review the structural interaction of RetGC1 with GCAP1 and RD3. I propose a two-state concerted model in which the dimeric RetGC1 allosterically switches between active and inactive conformational states with distinct quaternary structures that are oppositely stabilized by the binding of GCAP1 and RD3. The binding of Ca2+-free/Mg2+-bound GCAP1 is proposed to activate the cyclase by stabilizing RetGC1 in an active conformation (R-state), whereas Ca2+-bound GCAP1 and/or RD3 inhibit the cyclase by locking RetGC1 in an inactive conformation (T-state). Exposed hydrophobic residues in GCAP1 (residues H19, Y22, M26, F73, V77, W94) are essential for cyclase activation and could be targeted by rational drug design for the possible treatment of rod/cone dystrophies.