PDBsum entry 6dil

Hydrolase/hydrolase inhibitor

PDB id: 6dil

Contents

Protein chains

99 a.a.

Ligands

GOL ×3

ACT

TPV

Metals

_NA

_CL ×2

Waters ×146

PDB id:

6dil

Name:

Hydrolase/hydrolase inhibitor

Title:

HIV-1 protease with single mutation l76v in complex with tipranavir

Structure:

HIV-1 protease. Chain: a, b. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.48Å R-factor: 0.166 R-free: 0.214

Authors:

A.E.Wong-Sam,Y.-F.Wang,I.T.Weber

Key ref:

A.Wong-Sam et al. (2018). Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease. ACS Omega, 3, 12132-12140. PubMed id: 30288468

Date:

23-May-18 Release date: 17-Oct-18

Protein chains

P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: 1435 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 7 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

ACS Omega 3:12132-12140 (2018)

PubMed id: 30288468

Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease.

A.Wong-Sam, Y.F.Wang, Y.Zhang, A.K.Ghosh, R.W.Harrison, I.T.Weber.

ABSTRACT

Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PR_L76V). Compound 5 exhibited the best K_i value of 1.9 nM for PR_L76V, whereas the other three inhibitors had K_i values of 4.5-7.6 nM, 2-3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PR_L76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and Thr74 in the protein core, consistent with decreased stability. Inhibitors forming additional polar interactions with the flaps or dimer interface of PR_L76V were unable to compensate for the decrease in internal hydrophobic contacts. These structures provide insights for inhibitor design.