Structure of a G48H mutant of HIV-1 protease explains how glycine-48 replacements produce mutants resistant to inhibitor drugs.
The crystal structure of human immunodeficiency virus type 1 (HIV-1) protease mutant G48H with peptidic inhibitor U-89360E is described. Comparison with wild-type protease-inhibitor complex shows that mutation of flap residue 48 to histidine allows stabilizing van der Waals contacts between the side chains of His48 and Phe53 as well as between His48 and the P2' and P3' inhibitor subsites. The flap region is less mobile than in the wild-type enzyme. A model of saquinavir-resistant mutant protease G48V in complex with saquinavir predicts interactions similar to those found in the G48H crystal. Energetic calculations confirm the similarity of the His48 and Val48 interactions.
Hong
L
L
Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
Zhang
X J
XJ
Foundling
S
S
Hartsuck
J A
JA
Tang
J
J
D004352:Drug Resistance, Microbial; D005998:Glycine / Q000737:chemistry*; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D019258:Saquinavir / Q000737:chemistry
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; C101080:U 89360E; D016333:HIV Protease; D019258:Saquinavir; D005998:Glycine