PDBsum entry 6ogs

Viral protein/inhibitor

PDB id: 6ogs

Contents

Protein chain

99 a.a.

Ligands

PEG

GOL

JDY

SO4

Waters ×45

PDB id:

6ogs

Name:

Viral protein/inhibitor

Title:

X-ray crystal structure of darunavir-resistant HIV-1 protease (p30) in complex with grl-001

Structure:

Protease. Chain: a. Engineered: yes

Source:

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

Resolution:

1.27Å R-factor: 0.203 R-free: 0.210

Authors:

H.Bulut,S.I.Hattori,H.Aoki-Ogata,H.Hayashi,M.Aoki,A.K.Ghosh,H.Mitsuya

Key ref:

H.Bulut et al. (2020). Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity. Sci Rep, 10, 10664. PubMed id: 32606378 DOI: 10.1038/s41598-020-65993-z

Date:

03-Apr-19 Release date: 08-Apr-20

Protein chain

O38885  (O38885_9HIV1) -  Protease (Fragment) from Human immunodeficiency virus 1

Seq: 99 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1038/s41598-020-65993-z

Sci Rep 10:10664 (2020)

PubMed id: 32606378

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity.

H.Bulut, S.I.Hattori, H.Aoki-Ogata, H.Hayashi, D.Das, M.Aoki, D.A.Davis, K.V.Rao, P.R.Nyalapatla, A.K.Ghosh, H.Mitsuya.

ABSTRACT

HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2'-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PR_WT) and highly-multi-PI-resistance-associated PR_DRV^R_P51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2'-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier.