PDBsum entry 5t8h

Hydrolase/hydrolase inhibitor

PDB id: 5t8h

Contents

Protein chains

99 a.a.

Ligands

478

DOD ×124

PDB id:

5t8h

Name:

Hydrolase/hydrolase inhibitor

Title:

Joint x-ray/neutron structure of HIV-1 protease triple mutant (v32i, i47v,v82i) with amprenavir at ph 6.0

Structure:

Protease. Chain: a, b. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.85Å R-factor: 0.191 R-free: 0.214

Authors:

A.Y.Kovalevsky,O.O.Gerlits

Key ref:

O.Gerlits et al. (2017). Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K. J Med Chem, 60, 2018-2025. PubMed id: 28195728 DOI: 10.1021/acs.jmedchem.6b01767

Date:

07-Sep-16 Release date: 01-Mar-17

Protein chains

Q7SSI0  (Q7SSI0_9HIV1) -  Protease (Fragment) from Human immunodeficiency virus 1

Seq: 99 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.6b01767

J Med Chem 60:2018-2025 (2017)

PubMed id: 28195728

Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K.

O.Gerlits, D.A.Keen, M.P.Blakeley, J.M.Louis, I.T.Weber, A.Kovalevsky.

ABSTRACT

HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room-temperature joint X-ray/neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D(+) ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspartic acid residues. Comparison of the current XN structure with our previous XN structure of the wild-type HIV-1 protease-amprenavir complex suggests that the three mutations do not significantly alter the drug-enzyme interactions. This is in contrast to the observations in previous 100 K X-ray structures of these complexes that indicated loss of interactions by the drug with the triple mutant protease. These findings, thus, uncover limitations of structural analysis of drug binding using X-ray structures obtained at 100 K.