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Viral protein PDB id
2oc1
Jmol
Contents
Protein chains
183 a.a.
22 a.a.
151 a.a.
16 a.a.
Ligands
HU2
Metals
_ZN ×2
Waters ×98
PDB id:
2oc1
Name: Viral protein
Title: Structure of the hcv ns3/4a protease inhibitor cvs4819
Structure: Hepatitis c virus. Chain: a, c. Engineered: yes. Hepatitis c virus. Chain: b, d. Engineered: yes. Mutation: yes
Source: Hepatitis c virus. Organism_taxid: 11103. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes
Resolution:
2.70Å     R-factor:   0.189     R-free:   0.259
Authors: A.J.Prongay,Z.Guo,N.Yao,T.Fischmann,C.Strickland,J.Myers,Jr. P.C.Weber,B.Malcolm,B.M.Beyer,R.Ingram,J.Pichardo,Z.Hong, W.W.Prosise,L.Ramanathan,S.S.Taremi,T.Yarosh-Tomaine,R.Zhan M.Senior,R.Yang,A.Arasappan,F.Bennett,S.F.Bogen,K.Chen,E.Ja R.G.Love,A.K.Saksena,S.Venkatraman,V.Girijavallabhan,F.G.Nj V.Madison
Key ref: A.J.Prongay et al. (2007). Discovery of the HCV NS3/4A Protease Inhibitor (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key Steps in Structure-Based Optimization. J Med Chem, 50, 2310-2318. PubMed id: 17444623 DOI: 10.1021/jm060173k
Date:
20-Dec-06     Release date:   31-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9ELS8  (Q9ELS8_9HEPC) -  Genome polyprotein
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		3011 a.a.
183 a.a.*
Protein chain
Pfam   ArchSchema ?
Q9QP06  (Q9QP06_9HEPC) -  Genome polyprotein
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		3010 a.a.
22 a.a.*
Protein chain
Pfam   ArchSchema ?
Q9ELS8  (Q9ELS8_9HEPC) -  Genome polyprotein
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		3011 a.a.
151 a.a.*
Protein chain
Pfam   ArchSchema ?
Q9QP06  (Q9QP06_9HEPC) -  Genome polyprotein
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		3010 a.a.
16 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 7 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     transformation of host cell by virus   2 terms 
  Biochemical function     catalytic activity     2 terms  

 

 
DOI no: 10.1021/jm060173k J Med Chem 50:2310-2318 (2007)
PubMed id: 17444623  
 
 
Discovery of the HCV NS3/4A Protease Inhibitor (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key Steps in Structure-Based Optimization.
A.J.Prongay, Z.Guo, N.Yao, J.Pichardo, T.Fischmann, C.Strickland, J.Myers, P.C.Weber, B.M.Beyer, R.Ingram, Z.Hong, W.W.Prosise, L.Ramanathan, S.S.Taremi, T.Yarosh-Tomaine, R.Zhang, M.Senior, R.S.Yang, B.Malcolm, A.Arasappan, F.Bennett, S.L.Bogen, K.Chen, E.Jao, Y.T.Liu, R.G.Lovey, A.K.Saksena, S.Venkatraman, V.Girijavallabhan, F.G.Njoroge, V.Madison.
 
  ABSTRACT  
 
The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21345680 N.T.Doncheva, K.Klein, F.S.Domingues, and M.Albrecht (2011).
Analyzing and visualizing residue networks of protein structures.
  Trends Biochem Sci, 36, 179-182.  
21084633 K.P.Romano, A.Ali, W.E.Royer, and C.A.Schiffer (2010).
Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.
  Proc Natl Acad Sci U S A, 107, 20986-20991.
PDB codes: 3m5l 3m5m 3m5n 3m5o
20176898 O.Lenz, T.Verbinnen, T.I.Lin, L.Vijgen, M.D.Cummings, J.Lindberg, J.M.Berke, P.Dehertogh, E.Fransen, A.Scholliers, K.Vermeiren, T.Ivens, P.Raboisson, M.Edlund, S.Storm, L.Vrang, H.de Kock, G.C.Fanning, and K.A.Simmen (2010).
In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
  Antimicrob Agents Chemother, 54, 1878-1887.  
21243082 S.Margeridon-Thermet, and R.W.Shafer (2010).
Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C.
  Viruses, 2, 2696-2739.  
19159012 D.Ekonomiuk, X.C.Su, K.Ozawa, C.Bodenreider, S.P.Lim, Z.Yin, T.H.Keller, D.Beer, V.Patel, G.Otting, A.Caflisch, and D.Huang (2009).
Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking.
  PLoS Negl Trop Dis, 3, e356.  
19390331 G.Morsica, S.Bagaglio, C.Uberti-Foppa, L.Galli, and A.Lazzarin (2009).
Detection of hepatitis C mutants with natural resistance to NS3/4A protease inhibitors in HIV/HCV-coinfected individuals treated with antiretroviral therapy.
  J Acquir Immune Defic Syndr, 51, 106-108.  
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.  
18421139 V.Madison, A.J.Prongay, Z.Guo, N.Yao, J.Pichardo, T.Fischmann, C.Strickland, J.Myers, P.C.Weber, B.M.Beyer, R.Ingram, Z.Hong, W.W.Prosise, L.Ramanathan, S.S.Taremi, T.Yarosh-Tomaine, R.Zhang, M.Senior, R.S.Yang, B.Malcolm, A.Arasappan, F.Bennett, S.L.Bogen, K.Chen, E.Jao, Y.T.Liu, R.G.Lovey, A.K.Saksena, S.Venkatraman, V.Girijavallabhan, and F.G.Njoroge (2008).
Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034.
  J Synchrotron Radiat, 15, 204-207.  
18049474 E.De Clercq (2007).
The design of drugs for HIV and HCV.
  Nat Rev Drug Discov, 6, 1001-1018.  
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. Where a reference describes a PDB structure, the PDB codes are shown on the right.