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PDBsum entry 1rgq

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protein ligands metals Protein-protein interface(s) links
Viral protein, hydrolase PDB id
1rgq
Jmol
Contents
Protein chains
154 a.a. *
186 a.a. *
22 a.a. *
17 a.a. *
Ligands
AKP
Metals
_ZN ×2
* Residue conservation analysis
PDB id:
1rgq
Name: Viral protein, hydrolase
Title: M9a hcv protease complex with pentapeptide keto-amide inhibi
Structure: Ns3 protease. Chain: a, b. Fragment: residues 1027-1207. Engineered: yes. Ns4a peptide. Chain: c, d. Engineered: yes
Source: Hepatitis c virus. Organism_taxid: 11103. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide was chemically synthesized. The of the peptide is naturally found in hepatitis c virus
Biol. unit: Tetramer (from PQS)
Resolution:
2.90Å     R-factor:   0.279     R-free:   0.312
Authors: Y.Liu,V.S.Stoll,P.L.Richardson,A.Saldivar,J.L.Klaus,A.Molla, W.Kohlbrenner,W.M.Kati
Key ref: Y.Liu et al. (2004). Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure. Arch Biochem Biophys, 421, 207-216. PubMed id: 14984200 DOI: 10.1016/j.abb.2003.11.013
Date:
12-Nov-03     Release date:   19-Oct-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P27958  (POLG_HCVH) -  Genome polyprotein
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
3011 a.a.
154 a.a.*
Protein chain
Pfam   ArchSchema ?
P27958  (POLG_HCVH) -  Genome polyprotein
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
3011 a.a.
186 a.a.*
Protein chain
Pfam   ArchSchema ?
O39914  (O39914_9HEPC) -  Non-structural protein 4a/b (Fragment)
Seq:
Struc:
88 a.a.
22 a.a.*
Protein chain
Pfam   ArchSchema ?
O39914  (O39914_9HEPC) -  Non-structural protein 4a/b (Fragment)
Seq:
Struc:
88 a.a.
17 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 16 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 2: Chains A, B: E.C.2.7.7.48  - RNA-directed Rna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1)
Nucleoside triphosphate
+ RNA(n)
= diphosphate
+ RNA(n+1)
   Enzyme class 3: Chains A, B: E.C.3.4.21.98  - Hepacivirin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'.
   Enzyme class 4: Chains A, B: E.C.3.6.1.15  - Nucleoside-triphosphate phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: NTP + H2O = NDP + phosphate
NTP
+ H(2)O
= NDP
+ phosphate
   Enzyme class 5: Chains A, B: E.C.3.6.4.13  - Rna helicase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + H2O = ADP + phosphate
ATP
+ H(2)O
= ADP
+ phosphate
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     transformation of host cell by virus   2 terms 
  Biochemical function     catalytic activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.abb.2003.11.013 Arch Biochem Biophys 421:207-216 (2004)
PubMed id: 14984200  
 
 
Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure.
Y.Liu, V.S.Stoll, P.L.Richardson, A.Saldivar, J.L.Klaus, A.Molla, W.Kohlbrenner, W.M.Kati.
 
  ABSTRACT  
 
A series of novel peptidyl-alpha-ketoamide compounds were evaluated as inhibitors of the deltaNS3-NS4A serine protease from the hepatitis C virus. These peptidyl-alpha-ketoamide inhibitors with Ki values ranging from 0.17 nM to 5.6 microM exhibited slow-binding inhibition. Kinetic studies established one-step kinetic mechanisms and dissociation rate constants in the 3-7 x 10(-5) s(-1) range for these compounds. The association rate constants, which ranged from 10 to 263,000 M(-1) s(-1), were responsible for the greater than four order of magnitude overall binding affinity range exhibited by this series. An X-ray crystal structure of a protease-inhibitor complex revealed an unusual interaction between the oxyanion of the adduct and the protein as well as a significant movement in the S1' region of the protein loop comprising residues 35-42. These results are quite different from peptidyl-alpha-ketoacid inhibition of HCV protease, which reportedly undergoes no notable conformational changes and proceeds with a two-step slow-binding kinetic mechanism.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19395595 P.Qiu, V.Sanfiorenzo, S.Curry, Z.Guo, S.Liu, A.Skelton, E.Xia, C.Cullen, R.Ralston, J.Greene, and X.Tong (2009).
Identification of HCV protease inhibitor resistance mutations by selection pressure-based method.
  Nucleic Acids Res, 37, e74.  
17869377 R.De Francesco, and A.Carfí (2007).
Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus.
  Adv Drug Deliv Rev, 59, 1242-1262.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.