6OGP
X-ray crystal structure of wild type HIV-1 protease in complex with GRL-063
Summary for 6OGP
| Entry DOI | 10.2210/pdb6ogp/pdb |
| Descriptor | Protease, 1,2-ETHANEDIOL, (3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl {(2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-[(2-methylpropyl)({2-[(propan-2-yl)amino]-1,3-benzoxazol-6-yl}sulfonyl)amino]butan-2-yl}carbamate, ... (4 entities in total) |
| Functional Keywords | inhibitor, viral protein, viral protein-inhibitor complex, viral protein/inhibitor |
| Biological source | Human immunodeficiency virus 1 |
| Total number of polymer chains | 1 |
| Total formula weight | 11585.62 |
| Authors | Bulut, H.,Hattori, S.I.,Aoki-Ogata, H.,Hayashi, H.,Aoki, M.,Ghosh, A.K.,Mitsuya, H. (deposition date: 2019-04-03, release date: 2020-04-08, Last modification date: 2023-10-11) |
| Primary citation | Bulut, H.,Hattori, S.I.,Aoki-Ogata, H.,Hayashi, H.,Das, D.,Aoki, M.,Davis, D.A.,Rao, K.V.,Nyalapatla, P.R.,Ghosh, A.K.,Mitsuya, H. 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, 10:10664-10664, 2020 Cited by PubMed 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) and highly-multi-PI-resistance-associated PR 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. PubMed: 32606378DOI: 10.1038/s41598-020-65993-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.53 Å) |
Structure validation
Download full validation report
