Abstract
The nonmevalonate pathway is responsible for isoprenoid production in microbes, including H. pylori, M. tuberculosis and P. falciparum, but is nonexistent in humans, thus providing a desirable route for antibacterial and antimalarial drug discovery. We coordinate a structural study of IspH, a [4Fe-4S] protein responsible for converting HMBPP to IPP and DMAPP in the ultimate step in the nonmevalonate pathway. By performing accelerated molecular dynamics simulations on both substrate-free and HMBPP-bound [Fe4S4]2+ IspH, we elucidate how substrate binding alters the dynamics of the protein. Using principal component analysis, we note that while substrate-free IspH samples various open and closed conformations, the closed conformation observed experimentally for HMBPP-bound IspH is inaccessible in the absence of HMBPP. In contrast, simulations with HMBPP bound are restricted from accessing the open states sampled by the substrate-free simulations. Further investigation of the substrate-free simulations reveals large fluctuations in the HMBPP binding pocket, as well as allosteric pocket openings – both of which are achieved through the hinge motions of the individual domains in IspH. Coupling these findings with solvent mapping and various structural analyses reveals alternative druggable sites that may be exploited in future drug design efforts.
Highlights
In the past couple decades, antimicrobial drug resistance has risen dramatically and greatly hampered the efficacy of currently available therapies for bacterial and malarial infections [1,2,3,4,5,6,7,8,9]
Isoprenoids comprise essential metabolites derived from the 5-carbon biomolecules, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP, Figure 1), examples of which include sterols that provide structural support to membranes, chlorophylls used in photosynthesis, and quinones that participate in electron transport chains [11,12,13,14]
The large changes in root-mean-square deviation (RMSD) correspond to opening and closing motions of the D2 and D3 domains, providing a more dynamic description of the [Fe4S4]2+(open, substrate-free) state than is acquired from a static X-ray structure
Summary
In the past couple decades, antimicrobial drug resistance has risen dramatically and greatly hampered the efficacy of currently available therapies for bacterial and malarial infections [1,2,3,4,5,6,7,8,9]. Beyond the common problems associated with decreased lifetimes for drug efficacy due to rapid development of resistance [1,2,5,6,9], advances in the fight against bacterial and malarial infections have been plagued by diminished attention from major pharmaceutical companies toward the development of new therapies and drugs [4,5,10]. Animals acquire IPP and DMAPP in a distinctive manner via a mevalonate-dependent pathway. Given this metabolic difference, the proteins involved in the nonmevalonate pathway provide novel targets for the development of antibacterial and antimalarial drugs that are both broadly specific to pathogenic species such as H. pylori, M. tuberculosis and P. falciparum and without known human analogs [15,16,17,18]
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