PDBsum entry: 2o8m

Viral protein

PDB id: 2o8m

Contents

Protein chains

185 a.a. *

155 a.a. *

23 a.a. *

18 a.a. *

Metals

_NA ×2

_ZN ×2

Waters ×235

* Residue conservation analysis

PDB id:

2o8m

Name:

Viral protein

Title:

Crystal structure of the s139a mutant of hepatitis c virus ns3/4a protease

Structure:

Protease. Chain: a, b. Engineered: yes. Mutation: yes. Protease. Chain: c, d. Engineered: yes

Source:

Hepatitis c virus. Organism_taxid: 11103. Gene: hcv. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes

Resolution:

2.00Å R-factor: 0.194 R-free: 0.228

Authors:

T.O.Fischmann,A.J.Prongay,V.M.Madison,N.Yao

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:

12-Dec-06 Release date: 09-Oct-07

Protein chain

Q9ELS8  (Q9ELS8_9HEPC) -  Genome polyprotein

Seq: 3011 a.a.

Struc: 185 a.a.*

Protein chain

Q9ELS8  (Q9ELS8_9HEPC) -  Genome polyprotein

Seq: 3011 a.a.

Struc: 155 a.a.*

Protein chain

P27958  (POLG_HCVH) -  Genome polyprotein

Seq: 3011 a.a.

Struc: 23 a.a.*

Protein chain

P27958  (POLG_HCVH) -  Genome polyprotein

Seq: 3011 a.a.

Struc: 18 a.a.*

* PDB and UniProt seqs differ at 14 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains C, D: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1)
• Enzyme class 2: Chains C, D: E.C.3.4.21.98 - Hepacivirin.
• 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 3: Chains C, D: E.C.3.6.1.15 - Nucleoside-triphosphatase.
• Reaction: NTP + H₂O = NDP + phosphate
• Enzyme class 4: Chains C, D: E.C.3.6.4.13 - Rna helicase.
• Reaction: ATP + H₂O = 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 

• Biological process: transformation of host cell by virus (2 terms)
• Biochemical function: catalytic activity (2 terms)

reference

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.