2FV5

Crystal structure of TACE in complex with IK682

Summary for 2FV5

• Entry DOI: 10.2210/pdb2fv5/pdb
• Related: 1bkc 2ddf
• Descriptor: ADAM 17, ZINC ION, (2R)-N-HYDROXY-2-[(3S)-3-METHYL-3-{4-[(2-METHYLQUINOLIN-4-YL)METHOXY]PHENYL}-2-OXOPYRROLIDIN-1-YL]PROPANAMIDE, ... (4 entities in total)
• Functional Keywords: tace adam17 zn-endopeptidase, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P78536
• Total number of polymer chains: 2
• Total formula weight: 59759.49

Authors

Orth, P.,Niu, X. (deposition date: 2006-01-30, release date: 2006-07-04, Last modification date: 2024-10-16)

Primary citation

Niu, X.,Umland, S.,Ingram, R.,Beyer, B.M.,Liu, Y.H.,Sun, J.,Lundell, D.,Orth, P.
IK682, a tight binding inhibitor of TACE.
Arch.Biochem.Biophys., 451:43-50, 2006

PubMed 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.

PubMed: 16762314
DOI: 10.1016/j.abb.2006.03.034

Experimental method

X-RAY DIFFRACTION (2.1 Å)