PDBsum entry 2qnq

Hydrolase

PDB id: 2qnq

Contents

Protein chains

99 a.a. *

Ligands

QN3

Metals

_CL ×3

Waters ×70

* Residue conservation analysis

PDB id:

2qnq

Name:

Hydrolase

Title:

HIV-1 protease in complex with a chloro decorated pyrrolidine-based inhibitor

Structure:

Gag-pol polyprotein (pr160gag-pol). Chain: a, b. Fragment: HIV-1 retropepsin. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: gag-pol. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.205 R-free: 0.239

Authors:

J.Boettcher,A.Blum,A.Heine,W.E.Diederich,G.Klebe

Key ref:

A.Blum et al. (2008). Structure-guided design of C2-symmetric HIV-1 protease inhibitors based on a pyrrolidine scaffold. J Med Chem, 51, 2078-2087. PubMed id: 18348517

Date:

19-Jul-07 Release date: 15-Apr-08

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.

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

J Med Chem 51:2078-2087 (2008)

PubMed id: 18348517

Structure-guided design of C2-symmetric HIV-1 protease inhibitors based on a pyrrolidine scaffold.

A.Blum, J.Böttcher, A.Heine, G.Klebe, W.E.Diederich.

ABSTRACT

Infections with the human immunodeficiency virus, which inevitably lead to the development of AIDS, are still among the most serious global health problems causing more than 2.5 million deaths per year. In the pathophysiological processes of this pandemic, HIV protease has proven to be an invaluable drug target because of its essential role in the virus' replication process. By use of pyrrolidine as core structure, symmetric 3,4-bis-N-alkylsulfonamides were designed and synthesized enantioselectively from D-(-)-tartaric acid as a new class of HIV protease inhibitors. Structure-guided design using the cocrystal structure of an initial lead as starting point resulted in a second series of inhibitors with improved affinity. The binding modes of four representatives were determined by X-ray crystallography to elucidate the underlying factors accounting for the SAR. With this information for further rational design, the combination of suitable side chains resulted in a final inhibitor showing a significantly improved affinity of K(i) = 74 nM.