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3cki
From Proteopedia
| 3cki, resolution 2.30Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Sites: | |||||||||
| Ligands: | , | ||||||||
| Gene: | ADAM17, CSVP, TACE (Homo sapiens), TIMP3 (Homo sapiens) | ||||||||
| Activity: | ADAM 17 endopeptidase, with EC number 3.4.24.86 | ||||||||
| Domains: | ZnMc_TACE_like | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
Crystal structure of the TACE-N-TIMP-3 complex
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.
Structural Determinants of the ADAM Inhibition by TIMP-3: Crystal Structure of the TACE-N-TIMP-3 Complex., Wisniewska M, Goettig P, Maskos K, Belouski E, Winters D, Hecht R, Black R, Bode W, J Mol Biol. 2008 Jul 7. PMID:18638486
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Disease
Known disease associated with this structure: Sorsby fundus dystrophy OMIM:[188826]
About this Structure
3CKI is a 2 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- 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. 2008 Sep 19;381(5):1307-19. Epub 2008 Jul 7. PMID:18638486 doi:10.1016/j.jmb.2008.06.088
Page seeded by OCA on Tue Feb 17 20:14:14 2009
Categories: ADAM 17 endopeptidase | Homo sapiens | Belouski, E. | Black, R. | Bode, W. | Goettig, P. | Hecht, R. | Maskos, K. | Winters, D. | Wisniewska, M. | Alternative splicing | Catalytic zinc | Cleavage on pair of basic residue | Disease mutation | Extra-cellular matrix | Extracellular matrix | Glycoprotein | Hydrolase | Hydrolase inhibitor | Membrane | Metal-binding | Metalloenzyme inhibitor | Metalloprotease | Metalloprotease inhibitor | Notch signaling pathway | Phosphoprotein | Protease | Sa-sb loop | Secreted | Sensory transduction | Sh3-binding | Transmembrane | Vision | Zymogen
