1AXA

ACTIVE-SITE MOBILITY IN HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE AS DEMONSTRATED BY CRYSTAL STRUCTURE OF A28S MUTANT

Summary for 1AXA

• Entry DOI: 10.2210/pdb1axa/pdb
• Descriptor: HIV-1 PROTEASE, N-[[1-[N-ACETAMIDYL]-[1-CYCLOHEXYLMETHYL-2-HYDROXY-4-ISOPROPYL]-BUT-4-YL]-CARBONYL]-GLUTAMINYL-ARGINYL-AMIDE (3 entities in total)
• Functional Keywords: hiv protease, mutant, aspartic protease, hydrolase, acid proteinase, aspartyl protease
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22833.04

Authors

Hong, L.,Hartsuck, J.A.,Foundling, S.,Ermolieff, J.,Tang, J. (deposition date: 1997-10-13, release date: 1998-04-15, Last modification date: 2024-02-07)

Primary citation

Hong, L.,Hartsuck, J.A.,Foundling, S.,Ermolieff, J.,Tang, J.
Active-site mobility in human immunodeficiency virus, type 1, protease as demonstrated by crystal structure of A28S mutant.
Protein Sci., 7:300-305, 1998

PubMed Abstract: The mutation Ala28 to serine in human immunodeficiency virus, type 1, (HIV-1) protease introduces putative hydrogen bonds to each active-site carboxyl group. These hydrogen bonds are ubiquitous in pepsin-like eukaryotic aspartic proteases. In order to understand the significance of this difference between HIV-1 protease and homologous, eukaryotic aspartic proteases, we solved the three-dimensional structure of A28S mutant HIV-1 protease in complex with a peptidic inhibitor U-89360E. The structure has been determined to 2.0 A resolution with an R factor of 0.194. Comparison of the mutant enzyme structure with that of the wild-type HIV-1 protease bound to the same inhibitor (Hong L, Treharne A, Hartsuck JA, Foundling S, Tang J, 1996, Biochemistry 35:10627-10633) revealed double occupancy for the Ser28 hydroxyl group, which forms a hydrogen bond either to one of the oxygen atoms of the active-site carboxyl or to the carbonyl oxygen of Asp30. We also observed marked changes in orientation of the Asp25 catalytic carboxyl groups, presumably caused by the new hydrogen bonds. These observations suggest that catalytic aspartyl groups of HIV-1 protease have significant conformational flexibility unseen in eukaryotic aspartic proteases. This difference may provide an explanation for some unique catalytic properties of HIV-1 protease.

PubMed: 9521105

Experimental method

X-RAY DIFFRACTION (2 Å)