title: Conformational landscape of the human immunodeficiency virus type 1 reverse transcriptase non-nucleoside inhibitor binding pocket: lessons for inhibitor design from a cluster analysis of many crystal structures.
abstract: Clustering of 99 available X-ray crystal structures of HIV-1 reverse transcriptase (RT) at the flexible non-nucleoside inhibitor binding pocket (NNIBP) provides information about features of the conformational landscape for binding non-nucleoside inhibitors (NNRTIs), including effects of mutation and crystal forms. The ensemble of NNIBP conformations is separated into eight discrete clusters based primarily on the position of the functionally important primer grip, the displacement of which is believed to be one of the mechanisms of inhibition of RT. Two of these clusters are populated by structures in which the primer grip exhibits novel conformations that differ from the predominant cluster by over 4 A and are induced by the unique inhibitors capravirine and rilpivirine/TMC278. This work identifies a new conformation of the NNIBP that may be used to design NNRTIs. It can also be used to guide more complete exploration of the NNIBP free energy landscape using advanced sampling techniques.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, USA.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Paris
authors.forename: Omar
authors.initials: O
authors.lastname: Haq
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Felts
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Levy
mesh_terms: D001665:Binding Sites; D016000:Cluster Analysis; D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D008024:Ligands; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase