PDBsum entry 3bc4

Hydrolase

PDB id: 3bc4

Contents

Protein chain

99 a.a. *

Ligands

LLG ×2

DMS

Waters ×70

* Residue conservation analysis

PDB id:

3bc4

Name:

Hydrolase

Title:

I84v HIV-1 protease in complex with a pyrrolidine diester

Structure:

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

Source:

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

Resolution:

1.82Å R-factor: 0.193 R-free: 0.241

Authors:

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

Key ref:

J.Böttcher et al. (2008). Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors. Chemmedchem, 3, 1337-1344. PubMed id: 18720485

Date:

12-Nov-07 Release date: 02-Sep-08

Protein chain

P04587  (POL_HV1B5) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH5)

Seq: 1447 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

Chemmedchem 3:1337-1344 (2008)

PubMed id: 18720485

Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors.

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

ABSTRACT

HIV protease is a well-established drug target in antiviral chemotherapy. Immense research efforts have been made to discover effective inhibitors, thus making the enzyme one of the most studied and best characterized proteins. Although the protease exhibits high flexibility, all approved drugs target virtually the same protein conformation. The development of viral cross-resistance demands the generation of inhibitors with novel scaffolds and deviating modes of binding. Herein we report the design and the short, high-yielding stereoselective synthesis of a series of chiral, symmetric pyrrolidine-based inhibitors targeting the open-flap conformation of the protease. The obtained co-crystal structure with one derivative provides a valuable starting point for further inhibitor design.