PDBsum entry 1rtl

Viral protein complex

PDB id: 1rtl

Contents

Protein chains

180 a.a. *

153 a.a. *

21 a.a. *

16 a.a. *

Ligands

CPX

Metals

_ZN ×2

Waters ×102

* Residue conservation analysis

PDB id:

1rtl

Name:

Viral protein complex

Title:

Crystal structure of hcv ns3 protease domain: ns4a peptide complex with covalently bound pyrrolidine-5,5-translactam inhibitor

Structure:

Ns3 protease/helicase. Chain: a, b. Fragment: protease domain. Engineered: yes. Ns4a cofactor. Chain: c, d. Fragment: residues 21-39. Engineered: yes

Source:

Hepatitis c virus. Organism_taxid: 11103. Gene: h strain. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence of the protein is naturally found in hepatitis c virus type 1b.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.75Å R-factor: 0.182 R-free: 0.234

Authors:

T.Skarzynski,D.O.N.Somers

Key ref:

M.J.Slater et al. (2003). Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease. Org Lett, 5, 4627-4630. PubMed id: 14627400

Date:

10-Dec-03 Release date: 14-Dec-04

Protein chain

P26664  (POLG_HCV1) -  Genome polyprotein from Hepatitis C virus genotype 1a (isolate 1)

Seq: 3011 a.a.

Struc: 180 a.a.*

Protein chain

P26664  (POLG_HCV1) -  Genome polyprotein from Hepatitis C virus genotype 1a (isolate 1)

Seq: 3011 a.a.

Struc: 153 a.a.*

Protein chain

O39914  (O39914_9HEPC) -  Non-structural protein 4a/b (Fragment) from Hepacivirus hominis

Seq: 88 a.a.

Struc: 21 a.a.*

Protein chain

O39914  (O39914_9HEPC) -  Non-structural protein 4a/b (Fragment) from Hepacivirus hominis

Seq: 88 a.a.

Struc: 16 a.a.*

* PDB and UniProt seqs differ at 10 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chains A, B: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 3: Chains A, B: 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 4: Chains A, B: E.C.3.4.22.- - ?????
• Enzyme class 5: Chains A, B: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 6: Chains A, B: E.C.3.6.4.13 - Rna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

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

Org Lett 5:4627-4630 (2003)

PubMed id: 14627400

Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease.

M.J.Slater, E.M.Amphlett, D.M.Andrews, P.Bamborough, S.J.Carey, M.R.Johnson, P.S.Jones, G.Mills, N.R.Parry, D.O.Somers, A.J.Stewart, T.Skarzynski.

ABSTRACT

[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.