PDBsum entry 2fv5

Hydrolase

PDB id: 2fv5

Contents

Protein chains

261 a.a. *

Ligands

541 ×2

Metals

_ZN ×2

Waters ×414

* Residue conservation analysis

PDB id:

2fv5

Name:

Hydrolase

Title:

Crystal structure of tace in complex with ik682

Structure:

Adam 17. Chain: a, b. Synonym: a disintegrin and metalloproteinase domain 17, tnf-alpha- converting enzyme, tnf-alpha convertase, snake venom-like protease, cd156b antigen. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: adam17, csvp, tace. Expressed in: trichoplusia ni. Expression_system_taxid: 7111

Resolution:

2.10Å R-factor: 0.218 R-free: 0.256

Authors:

P.Orth,X.Niu

Key ref:

X.Niu et al. (2006). IK682, a tight binding inhibitor of TACE. Arch Biochem Biophys, 451, 43-50. PubMed id: 16762314 DOI: 10.1016/j.abb.2006.03.034

Date:

30-Jan-06 Release date: 04-Jul-06

Protein chains

P78536  (ADA17_HUMAN) -  Disintegrin and metalloproteinase domain-containing protein 17 from Homo sapiens

Seq: 824 a.a.

Struc: 261 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.24.86 - Adam 17 endopeptidase.
• Cofactor: Zn(2+)

DOI no: 10.1016/j.abb.2006.03.034

Arch Biochem Biophys 451:43-50 (2006)

PubMed id: 16762314

IK682, a tight binding inhibitor of TACE.

X.Niu, S.Umland, R.Ingram, B.M.Beyer, Y.H.Liu, J.Sun, D.Lundell, P.Orth.

ABSTRACT

TNFalpha converting enzyme (TACE) is the major metalloproteinase for the processing of TNFalpha, a key inflammatory cytokine. IK682, a hydroxamate compound, was reported to be a potent and specific TACE inhibitor [J.J. Duan, L. Chen, Z.R. Wasserman, Z. Lu, R.Q. Liu, M.B. Covington, M. Qian, K.D. Hardman, R.L. Magolda, R.C. Newton, D.D. Christ, R.R. Wexler, C.P. Decicco, J. Med. Chem. 45 (2002) 4954-4957]. The binding kinetics of IK682 and the ectodomain of human TACE was examined. The k(on) of IK682 was determined as 1.1+/-0.3 x 10(8) M(-1) min(-1). No detectable dissociation of IK682 from TACE was observed following dialysis, dilution, and extensive washing over a maximum of 72 h. This was in contrast to the rapid dissociation of IK682 from ADAM10. LC/MS analysis of the TACE-IK682 complex after dissociation under denaturing conditions indicated that the tight binding is not due to covalent interaction. The X-ray crystal structure of TACE-IK682 complex revealed multiple binding points at the S1' and S3' sites and the movement of a loop (from Ala349 to Gly442) to accommodate the binding of the quinolinyl group of IK682 at the S3' pocket. The conformational changes of TACE may contribute significantly to the high affinity binding as a result of a more stable TACE-inhibitor complex.