3VF5
Crystal Structure of HIV-1 Protease Mutant I47V with novel P1'-Ligands GRL-02031
Summary for 3VF5
| Entry DOI | 10.2210/pdb3vf5/pdb |
| Related | 3H5B 3VF7 3VFA 3VFB |
| Descriptor | Protease, SODIUM ION, CHLORIDE ION, ... (7 entities in total) |
| Functional Keywords | protease inhibitor, p1'-ligand, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Human immunodeficiency virus type 1 (BRU ISOLATE) (HIV-1) |
| Cellular location | Gag-Pol polyprotein: Host cell membrane ; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03367 |
| Total number of polymer chains | 2 |
| Total formula weight | 22452.98 |
| Authors | Yu, X.X.,Wang, Y.F.,Chang, Y.C.E.,Weber, I.T. (deposition date: 2012-01-09, release date: 2012-11-21, Last modification date: 2023-09-13) |
| Primary citation | Chang, Y.C.,Yu, X.,Zhang, Y.,Tie, Y.,Wang, Y.F.,Yashchuk, S.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T. Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1'-pyrrolidinone ring. J.Med.Chem., 55:3387-3397, 2012 Cited by PubMed Abstract: GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1' (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25-1.55 Å were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PR(I47V), PR(L76V), PR(V82A), and PR(N88D). Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PR(I47V) and PR(L76V) and the altered charge of PR(N88D) are associated with significant local structural changes compared to the wild-type PR(WT), while substitution of alanine in PR(V82A) increases the size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PR(WT) with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1. PubMed: 22401672DOI: 10.1021/jm300072d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.25 Å) |
Structure validation
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