3CKI

Crystal structure of the TACE-N-TIMP-3 complex

Summary for 3CKI

• Entry DOI: 10.2210/pdb3cki/pdb
• Descriptor: ADAM 17, Metalloproteinase inhibitor 3, ZINC ION, ... (5 entities in total)
• Functional Keywords: extra-cellular matrix, catalytic zinc, sa-sb loop, alternative splicing, cleavage on pair of basic residues, glycoprotein, membrane, metal-binding, metalloprotease, notch signaling pathway, phosphoprotein, protease, sh3-binding, transmembrane, zymogen, disease mutation, extracellular matrix, metalloenzyme inhibitor, metalloprotease inhibitor, secreted, sensory transduction, vision, hydrolase, hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P78536; Secreted, extracellular space, extracellular matrix: P35625
• Total number of polymer chains: 2
• Total formula weight: 43016.13

Authors

Wisniewska, M.,Goettig, P.,Maskos, K.,Belouski, E.,Winters, D.,Hecht, R.,Black, R.,Bode, W. (deposition date: 2008-03-15, release date: 2008-08-05, Last modification date: 2024-11-20)

Primary citation

Wisniewska, M.,Goettig, P.,Maskos, K.,Belouski, E.,Winters, D.,Hecht, R.,Black, R.,Bode, W.
Structural determinants of the ADAM inhibition by TIMP-3: crystal structure of the TACE-N-TIMP-3 complex.
J.Mol.Biol., 381:1307-1319, 2008

PubMed Abstract: TIMP-3 (tissue inhibitor of metalloproteinases 3) is unique among the TIMP inhibitors, in that it effectively inhibits the TNF-alpha converting enzyme (TACE). In order to understand this selective capability of inhibition, we crystallized the complex formed by the catalytic domain of recombinant human TACE and the N-terminal domain of TIMP-3 (N-TIMP-3), and determined its molecular structure with X-ray data to 2.3 A resolution. The structure reveals that TIMP-3 exhibits a fold similar to those of TIMP-1 and TIMP-2, and interacts through its functional binding edge, which consists of the N-terminal segment and other loops, with the active-site cleft of TACE in a manner similar to that of matrix metalloproteinases (MMPs). Therefore, the mechanism of TIMP-3 binding toward TACE is not fundamentally different from that previously elucidated for the MMPs. The Phe34 phenyl side chain situated at the tip of the relatively short sA-sB loop of TIMP-3 extends into a unique hydrophobic groove of the TACE surface, and two Leu residues in the adjacent sC-connector and sE-sF loops are tightly packed in the interface allowing favourable interactions, in agreement with predictions obtained by systematic mutations by Gillian Murphy's group. The combination of favourable functional epitopes together with a considerable flexibility renders TIMP-3 an efficient TACE inhibitor. This structure might provide means to design more efficient TIMP inhibitors of TACE.

PubMed: 18638486
DOI: 10.1016/j.jmb.2008.06.088

Experimental method

X-RAY DIFFRACTION (2.3 Å)