Structure of a G48H Mutant of HIV-1 Protease Explains How Glycine-48 Replacements Produce Mutants Resistant to Inhibitor Drugs

Overview

Journal FEBS Lett

Specialty Biochemistry

Date 1998 Feb 5

PMID 9450540

Citations 5

Authors

L Hong

X J Zhang

S Foundling

J A Hartsuck

J Tang

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Investigating the genomic landscape of novel coronavirus (2019-nCoV) to identify non-synonymous mutations for use in diagnosis and drug design.

Tiwari M, Mishra D J Clin Virol. 2020; 128:104441.

PMID: 32425659 PMC: 7227581. DOI: 10.1016/j.jcv.2020.104441.

Analysis of HIV-1 CRF_01 A/E protease inhibitor resistance: structural determinants for maintaining sensitivity and developing resistance to atazanavir.

Clemente J, Coman R, Thiaville M, Janka L, Jeung J, Nukoolkarn S Biochemistry. 2006; 45(17):5468-77.

PMID: 16634628 PMC: 2518317. DOI: 10.1021/bi051886s.

Insights into saquinavir resistance in the G48V HIV-1 protease: quantum calculations and molecular dynamic simulations.

Wittayanarakul K, Aruksakunwong O, Saen-Oon S, Chantratita W, Parasuk V, Sompornpisut P Biophys J. 2004; 88(2):867-79.

PMID: 15542562 PMC: 1305161. DOI: 10.1529/biophysj.104.046110.

Inhibition and substrate recognition--a computational approach applied to HIV protease.

Vinkers H, de Jonge M, Daeyaert E, Heeres J, Koymans L, van Lenthe J J Comput Aided Mol Des. 2004; 17(9):567-81.

PMID: 14713189 DOI: 10.1023/b:jcam.0000005748.19093.e8.

Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.

King N, Melnick L, Prabu-Jeyabalan M, Nalivaika E, Gao Y, Nie X Protein Sci. 2002; 11(2):418-29.

PMID: 11790852 PMC: 2373441. DOI: 10.1110/ps.25502.