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PDBsum entry 4k4q

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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
4k4q
Jmol
Contents
Protein chains
99 a.a.
Ligands
NO3 ×6
BME
DMS ×2
3TL
06B
06B-06B
Waters ×78
PDB id:
4k4q
Name: Hydrolase/hydrolase inhibitor
Title: Tl-3 inhibited trp6ala HIV protease with 3-bromo-2,6-dimetho acid bound in flap site
Structure: HIV-1 protease. Chain: a, b. Engineered: yes. Mutation: yes
Source: Human immunodeficiency virus 1. HIV-1. Organism_taxid: 11683. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.80Å     R-factor:   0.197     R-free:   0.230
Authors: T.Tiefenbrunn,C.D.Stout
Key ref: T.Tiefenbrunn et al. (2014). Crystallographic fragment-based drug discovery: use of a brominated fragment library targeting HIV protease. Chem Biol Drug Des, 83, 141-148. PubMed id: 23998903 DOI: 10.1111/cbdd.12227
Date:
12-Apr-13     Release date:   18-Sep-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P12499  (POL_HV1Z2) -  Gag-Pol polyprotein
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1436 a.a.
99 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.7.49  - RNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
Deoxynucleoside triphosphate
+ DNA(n)
= diphosphate
+ DNA(n+1)
   Enzyme class 2: E.C.2.7.7.7  - DNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
Deoxynucleoside triphosphate
+ DNA(n)
= diphosphate
+ DNA(n+1)
   Enzyme class 3: E.C.3.1.13.2  - Exoribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      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.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 5: E.C.3.4.23.16  - HIV-1 retropepsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      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
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     aspartic-type endopeptidase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1111/cbdd.12227 Chem Biol Drug Des 83:141-148 (2014)
PubMed id: 23998903  
 
 
Crystallographic fragment-based drug discovery: use of a brominated fragment library targeting HIV protease.
T.Tiefenbrunn, S.Forli, M.Happer, A.Gonzalez, Y.Tsai, M.Soltis, J.H.Elder, A.J.Olson, C.D.Stout.
 
  ABSTRACT  
 
A library of 68 brominated fragments was screened against a new crystal form of inhibited HIV-1 protease in order to probe surface sites in soaking experiments. Often, fragments are weak binders with partial occupancy, resulting in weak, difficult-to-fit electron density. The use of a brominated fragment library addresses this challenge, as bromine can be located unequivocally via anomalous scattering. Data collection was carried out in an automated fashion using AutoDrug at SSRL. Novel hits were identified in the known surface sites: 3-bromo-2,6-dimethoxybenzoic acid (Br6) in the flap site and 1-bromo-2-naphthoic acid (Br27) in the exosite, expanding the chemistry of known fragments for development of higher affinity potential allosteric inhibitors. At the same time, mapping the binding sites of a number of weaker binding Br-fragments provides further insight into the nature of these surface pockets.