Abstract
A plethora of membrane proteins are found along the cell surface and on the convoluted labyrinth of membranes surrounding organelles. Since the advent of various structural biology techniques, a sub-population of these proteins has become accessible to investigation at near-atomic resolutions. The predominant bona fide methods for structure solution, X-ray crystallography and cryo-EM, provide high resolution in three-dimensional space at the cost of neglecting protein motions through time. Though structures provide various rigid snapshots, only an amorphous mechanistic understanding can be inferred from interpolations between these different static states. In this review, we discuss various techniques that have been utilized in observing dynamic conformational intermediaries that remain elusive from rigid structures. More specifically we discuss the application of structural techniques such as NMR, cryo-EM and X-ray crystallography in studying protein dynamics along with complementation by conformational trapping by specific binders such as antibodies. We finally showcase the strength of various biophysical techniques including FRET, EPR and computational approaches using a multitude of succinct examples from GPCRs, transporters and ion channels.
Highlights
A third of both pro- and eukaryotic proteomes consist of membrane proteins
From a theoretical perspective supported by experimental data for ion channels [1], or G-protein coupled receptors (GPCRs) [2], we can envision a combination of conformational states that remain in equilibrium
We present the remarkable undertakings by the scientific community integrating multidisciplinary efforts that elucidate the relationship between structure, dynamics, and function using GPCRs, ion channels and transporters as examples
Summary
A third of both pro- and eukaryotic proteomes consist of membrane proteins. Housed in a milieu of hydrophobic molecules, they serve as crucial contacts of communication between the cytoplasm and non-cytosolic environments, making them essential pharmaceutical targets. While membrane proteins are notoriously difficult to investigate at any level, high-resolution structures of these targets only became feasible at the very end of the twentieth century. Integral membrane proteins (IMPs), involved in transport and signal transduction, are highly dynamic, lipid-embedded entities that serve as molecular nano-machines controlling bi-directional transport of materials and information across the cell membrane. These physicochemical constraints necessitate a set of well-defined and specific movements, where the interplay between conformational dynamics and intrinsic flexibility becomes extremely important in defining their functionality. We present the remarkable undertakings by the scientific community integrating multidisciplinary efforts that elucidate the relationship between structure, dynamics, and function using GPCRs, ion channels and transporters as examples
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