PDBsum entry 3vf5

Hydrolase/hydrolase inhibitor

PDB id: 3vf5

Contents

Protein chains

99 a.a.

Ligands

ACT ×2

031

GOL

Metals

_NA ×2

_CL ×4

Waters ×205

PDB id:

3vf5

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of HIV-1 protease mutant i47v with novel p1'-ligands grl-02031

Structure:

Protease. Chain: a, b. Fragment: unp residues 501-599. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus type 1 (bru isolate). HIV-1. Organism_taxid: 11686. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.25Å R-factor: 0.148 R-free: 0.169

Authors:

X.X.Yu,Y.F.Wang,Y.C.E.Chang,I.T.Weber

Key ref:

Y.C.Chang et al. (2012). 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. PubMed id: 22401672

Date:

09-Jan-12 Release date: 21-Nov-12

Protein chains

P03367  (POL_HV1BR) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI)

Seq: 1447 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 2: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: E.C.3.1.13.2 - exoribonuclease H.
• Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
• Enzyme class 4: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 5: E.C.3.4.23.16 - HIV-1 retropepsin.
• Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 55:3387-3397 (2012)

PubMed id: 22401672

Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1'-pyrrolidinone ring.

Y.C.Chang, X.Yu, Y.Zhang, Y.Tie, Y.F.Wang, S.Yashchuk, A.K.Ghosh, R.W.Harrison, I.T.Weber.

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.