title: Structural Basis of Why Nelfinavir-Resistant D30N Mutant of HIV-1 Protease Remains Susceptible to Saquinavir.
abstract: Although anti-HIV-1 protease drugs nelfinavir (NFV) and saquinavir (SQV) share common functional groups, D30N is a major resistance mutation against NFV but remains susceptible to SQV. We have determined the crystal structure of D30N mutant-tethered HIV-1 protease in complex with SQV to 1.79 Å resolution. Structural analysis showed that SQV forms two direct hydrogen bonds with the main chain atoms of the residues Asp29 and Asp30 that are not observed in the D30N-NFV complex. Apart from maintaining these two main chain hydrogen bonds, the P2-asparagine of SQV forms an additional hydrogen bond to the mutated side chain of the residue 30. These could be the reasons why D30N is not a drug resistance mutation against SQV. This structure supports the previous studies showing that the interactions between a potential inhibitor and backbone atoms of the enzyme are important to maintain potency against drug-resistant HIV-1 protease.
authors.affiliation: Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Prashar
authors.affiliation: Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Bihani
authors.affiliation: Institut de Biologie Structurale Jean-Pierre Ebel, Groupe Synchrotron, Commissariat a l'Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, Universite de Grenoble Alpes, Grenoble, 38027, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Ferrer
authors.forename: Madhusoodan V
authors.initials: MV
authors.lastname: Hosur
mesh_terms: D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D005470:Fluorometry; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D019888:Nelfinavir / Q000737:chemistry* / Q000494:pharmacology*; D017510:Protein Folding; D019258:Saquinavir / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019888:Nelfinavir; D019258:Saquinavir
keywords: HIV-1 protease; X-ray crystallography; drug resistance; nelfinavir; saquinavir; susceptibility