title: Utilizing a dynamical description of IspH to aid in the development of novel antimicrobial drugs.
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.
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Blachly
authors.affiliation: Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America.
authors.forename: César A F
authors.initials: CA
authors.lastname: de Oliveira
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Williams
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, United States of America ; Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America ; Department of Pharmacology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry*; D020134:Catalytic Domain; D015195:Drug Design; D008024:Ligands; D008962:Models, Theoretical; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D008024:Ligands