6ogt | pdb_00006ogt

X-ray crystal structure of darunavir-resistant HIV-1 protease (P51) in complex with GRL-001

spinqualitylabelsall models 6ogt, resolution 1.21Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ogt is a 1 chain structure with sequence from 9hiv1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, GOL, JDY Gene: pol (9HIV1) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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 (PRWT) and highly-multi-PI-resistance-associated PRDRV(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. 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.,Bulut H, Hattori SI, Aoki-Ogata H, Hayashi H, Das D, Aoki M, Davis DA, Rao KV, Nyalapatla PR, Ghosh AK, Mitsuya H Sci Rep. 2020 Jun 30;10(1):10664. doi: 10.1038/s41598-020-65993-z. PMID:32606378 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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