PDBsum entry 2zeb

Hydrolase

PDB id: 2zeb

Contents

Protein chain

243 a.a. *

Ligands

11M ×4

Waters ×299

* Residue conservation analysis

PDB id:

2zeb

Name:

Hydrolase

Title:

Potent, nonpeptide inhibitors of human mast cell tryptase

Structure:

Tryptase beta 2. Chain: a, b, c, d. Fragment: unp residues 31-273. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tpsb2

Resolution:

2.50Å R-factor: 0.172 R-free: 0.225

Authors:

J.C.Spurlino,F.Lewandowski,C.Milligan

Key ref:

M.J.Costanzo et al. (2008). Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives. Bioorg Med Chem Lett, 18, 2114-2121. PubMed id: 18272363 DOI: 10.1016/j.bmcl.2008.01.093

Date:

08-Dec-07 Release date: 09-Dec-08

Protein chains

Q15661  (TRYB1_HUMAN) -  Tryptase alpha/beta-1 from Homo sapiens

Seq: 275 a.a.

Struc: 243 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.21.59 - tryptase.
• Reaction: Preferential cleavage: Arg-|-, Lys-|-, but with more restricted specificity than trypsin.

DOI no: 10.1016/j.bmcl.2008.01.093

Bioorg Med Chem Lett 18:2114-2121 (2008)

PubMed id: 18272363

Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives.

M.J.Costanzo, S.C.Yabut, H.C.Zhang, K.B.White, L.de Garavilla, Y.Wang, L.K.Minor, B.A.Tounge, A.N.Barnakov, F.Lewandowski, C.Milligan, J.C.Spurlino, W.M.Abraham, V.Boswell-Smith, C.P.Page, B.E.Maryanoff.

ABSTRACT

We have explored a series of spirocyclic piperidine amide derivatives (5) as tryptase inhibitors. Thus, 4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of 4 x tryptase revealed a hydrophobic pocket in the enzyme's active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.