PDBsum entry 4zro

Hydrolase/hydrolase inhibitor

PDB id: 4zro

Contents

Protein chains

299 a.a.

Ligands

BOC-SER-VAL-LEU-CEV ×4

DMS ×2

Waters ×547

PDB id:

4zro

Name:

Hydrolase/hydrolase inhibitor

Title:

2.1 a x-ray structure of fipv-3clpro bound to covalent inhibitor

Structure:

3c-like proteinase. Chain: a, b, c, d. Synonym: 3cl-pro, 3clp, m-pro, nsp5. Engineered: yes. Bounded inhibitor of n-(tert-butoxycarbonyl)-l-seryl-l- valyl-n-{(2s)-5-ethoxy-5-oxo-1-[(3s)-2-oxopyrrolidin-3-yl]pentan-2- yl}-l-leucinamide. Chain: e, f, g, h. Engineered: yes

Source:

Feline coronavirus (strain fipv wsu-79/1146). Fcov. Organism_taxid: 33734. Strain: fipv wsu-79/1146. Gene: rep, 1a-1b. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct.

Resolution:

2.06Å R-factor: 0.172 R-free: 0.231

Authors:

S.E.St John,A.D.Mesecar

Key ref:

S.E.St John et al. (2015). X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design. Bioorg Med Chem Lett, 25, 5072-5077. PubMed id: 26592814 DOI: 10.1016/j.bmcl.2015.10.023

Date:

12-May-15 Release date: 14-Oct-15

Protein chains

Q98VG9  (R1AB_FIPV) -  Replicase polyprotein 1ab from Feline coronavirus (strain FIPV WSU-79/1146)

Seq: 6709 a.a.

Struc: 299 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.1.1.57 - methyltransferase cap1.
• Reaction: a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside in mRNA + S-adenosyl-L-methionine = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)- (2'-O-methyl-ribonucleoside) in mRNA + S-adenosyl-L-homocysteine + H⁺
• Enzyme class 3: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 4: E.C.2.7.7.50 - mRNA guanylyltransferase.
• Reaction: a 5'-end diphospho-ribonucleoside in mRNA + GTP + H⁺ = a 5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA + diphosphate
• Enzyme class 5: E.C.3.1.13.- - ?????
• Enzyme class 6: E.C.3.4.19.12 - ubiquitinyl hydrolase 1.
• Reaction: Thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).
• Enzyme class 7: E.C.3.4.22.- - ?????
• Enzyme class 8: E.C.3.6.4.12 - Dna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺
• Enzyme class 9: E.C.3.6.4.13 - Rna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺
• Enzyme class 10: E.C.4.6.1.- - ?????

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

DOI no: 10.1016/j.bmcl.2015.10.023

Bioorg Med Chem Lett 25:5072-5077 (2015)

PubMed id: 26592814

X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design.

S.E.St John, M.D.Therkelsen, P.R.Nyalapatla, H.L.Osswald, A.K.Ghosh, A.D.Mesecar.

ABSTRACT

Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though it kills approximately 5% of cats in multi-cat households per year. In an effort to develop small molecule drugs targeting FIP for the treatment of cats, we screened a small set of designed peptidomimetic inhibitors for inhibition of FIPV-3CL(pro), identifying two compounds with low to sub-micromolar inhibition, compound 6 (IC50=0.59±0.06μM) and compound 7 (IC50=1.3±0.1μM). We determined the first X-ray crystal structure of FIPV-3CL(pro) in complex with the best inhibitor identified, compound 6, to a resolution of 2.10Å to better understand the structural basis for inhibitor specificity. Our study provides important insights into the structural requirements for the inhibition of FIPV-3CL(pro) by peptidomimetic inhibitors and expands the current structural knowledge of coronaviral 3CL(pro) architecture.