PDBsum entry 6dh6

Hydrolase/hydrolase inhibitor

PDB id: 6dh6

Contents

Protein chains

99 a.a.

Ligands

SO4 ×3

017

Waters ×181

PDB id:

6dh6

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of HIV-1 protease nl4-3 i50v mutant in complex with darunavir

Structure:

Protease. Chain: b, a. Engineered: yes

Source:

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

Resolution:

1.97Å R-factor: 0.177 R-free: 0.222

Authors:

G.J.Lockbaum,C.A.Schiffer

Key ref:

G.J.Lockbaum et al. (2019). Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease. ACS Infect Dis, 5, 316-325. PubMed id: 30543749 DOI: 10.1021/acsinfecdis.8b00336

Date:

18-May-18 Release date: 26-Dec-18

Protein chains

Q7ZCR0  (Q7ZCR0_9HIV1) -  Protease (Fragment) from Human immunodeficiency virus 1

Seq: 99 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1021/acsinfecdis.8b00336

ACS Infect Dis 5:316-325 (2019)

PubMed id: 30543749

Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.

G.J.Lockbaum, F.Leidner, L.N.Rusere, M.Henes, K.Kosovrasti, G.S.Nachum, E.A.Nalivaika, A.Ali, N.K.Yilmaz, C.A.Schiffer.

ABSTRACT

HIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken inhibitor binding to confer resistance. Darunavir (DRV) is the most potent HIV-1 protease inhibitor in clinic; resistance is limited, as DRV fits well within the substrate envelope. Nevertheless, resistance is observed due to hydrophobic changes at residues including I50, V82, and I84 that line the S1/S1' pocket within the active site. Through enzyme inhibition assays and a series of 12 crystal structures, we interrogated susceptibility of DRV and two potent analogues to primary S1' mutations. The analogues had modifications at the hydrophobic P1' moiety compared to DRV to better occupy the unexploited space in the S1' pocket where the primary mutations were located. Considerable losses of potency were observed against protease variants with I84V and I50V mutations for all three inhibitors. The crystal structures revealed an unexpected conformational change in the flap region of I50V protease bound to the analogue with the largest P1' moiety, indicating interdependency between the S1' subsite and the flap region. Collective analysis of protease-inhibitor interactions in the crystal structures using principle component analysis was able to distinguish inhibitor identity and relative potency solely based on van der Waals contacts. Our results reveal the complexity of the interplay between inhibitor P1' moiety and S1' mutations and validate principle component analyses as a useful tool for distinguishing resistance and inhibitor potency.