PDBsum entry 4yhq

Hydrolase/hydrolase inhibitor

PDB id: 4yhq

Contents

Protein chains

99 a.a.

Ligands

G10

GOL ×2

Metals

_Y1 ×4

_CL ×5

_NA

Waters ×175

PDB id:

4yhq

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of multidrug resistant clinical isolate pr20 with grl-5010a

Structure:

Protease. Chain: a, b. Synonym: pr, retropepsin. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus type 1 group m subtype. HIV-1. Organism_taxid: 11678. Strain: isolate pr20. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.30Å R-factor: 0.157 R-free: 0.210

Authors:

J.Agniswamy,I.T.Weber

Key ref:

J.Agniswamy et al. (2015). Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20. J Med Chem, 58, 5088-5095. PubMed id: 26010498 DOI: 10.1021/acs.jmedchem.5b00474

Date:

27-Feb-15 Release date: 10-Jun-15

Protein chains

P03366  (POL_HV1B1) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH10)

Seq: 1447 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 22 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.- - ?????
• Enzyme class 2: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 4: E.C.3.1.-.-
• Enzyme class 5: 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 6: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: 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

DOI no: 10.1021/acs.jmedchem.5b00474

J Med Chem 58:5088-5095 (2015)

PubMed id: 26010498

Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20.

J.Agniswamy, J.M.Louis, C.H.Shen, S.Yashchuk, A.K.Ghosh, I.T.Weber.

ABSTRACT

An extremely drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with two potent antiviral investigational inhibitors. GRL-5010A and GRL-4410A were designed to introduce hydrogen bond interactions with the flexible flaps of the PR by incorporating gem-difluorines and alkoxy, respectively, at the C4 position of the bis-THF of darunavir. PR20 provides an excellent model for high level resistance, since clinical inhibitors are >1000-fold less active on PR20 than on wild-type enzyme. GRL-5010A and GRL-4410A show inhibition constants of 4.3 ± 7.0 and 1.7 ± 1.8 nM, respectively, for PR20, compared to the binding affinity of 41 ± 1 nM measured for darunavir. Crystal structures of PR20 in complexes with the two inhibitors confirmed the new hydrogen bond interactions with Gly 48 in the flap of the enzyme. The two new compounds are more effective than darunavir in inhibiting mature PR20 and show promise for further development of antiviral agents targeting highly resistant PR mutants.