PDBsum entry 3e8r

Hydrolase

PDB id

3e8r

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Contents

			Protein chains

					251 a.a. *

			Ligands

					615-INN


					615


					CIT

			Metals

					_ZN ×2

			Waters ×449

* Residue conservation analysis

PDB id:

3e8r

Links

Name:

Hydrolase

Title:

Crystal structure of catalytic domain of tace with hydroxamate inhibitor

Structure:

Adam 17. Chain: a, b. Fragment: catalytic domain, unp residues 215-477. Synonym: a disintegrin and metalloproteinase domain 17, tnf-alpha- converting enzyme, tnf-alpha convertase, snake venom-like protease. Engineered: yes. Mutation: yes

Source:

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

Resolution:

1.90Å

R-factor:

0.190

R-free:

0.226

Authors:

P.Orth

Key ref:

R.D.Mazzola et al. (2008). Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors. Part II: optimization of the S3' pocket. Bioorg Med Chem Lett, 18, 5809-5814. PubMed id: 18835710

Date:

20-Aug-08

Release date:

21-Oct-08

PROCHECK

	Headers

	References

Protein chains

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

Seq: Struc:

Seq: Struc:					824 a.a. 251 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 3 residue positions (black crosses)



		Enzyme reactions

Enzyme class:

E.C.3.4.24.86 - Adam 17 endopeptidase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Cofactor:

Zn(2+)

	Bioorg Med Chem Lett 18:5809-5814 (2008)
PubMed id: 18835710

Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors. Part II: optimization of the S3' pocket.
R.D.Mazzola, Z.Zhu, L.Sinning, B.McKittrick, B.Lavey, J.Spitler, J.Kozlowski, S.Neng-Yang, G.Zhou, Z.Guo, P.Orth, V.Madison, J.Sun, D.Lundell, X.Niu.

ABSTRACT

A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20871631

T.Maretzky, W.Zhou, X.Y.Huang, and C.P.Blobel (2011).
A transforming Src mutant increases the bioavailability of EGFR ligands via stimulation of the cell-surface metalloproteinase ADAM17.

Oncogene, 30, 611-618.

20486929

M.S.Bahia, and O.Silakari (2010).
Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

Chem Biol Drug Des, 75, 415-443.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.