PDBsum entry 3f8s

Hydrolase

PDB id: 3f8s

Contents

Protein chain

728 a.a. *

Ligands

NAG-NAG ×4

NAG ×3

PF2 ×2

* Residue conservation analysis

PDB id:

3f8s

Name:

Hydrolase

Title:

Crystal structure of dipeptidyl peptidase iv in complex with inhibitor

Structure:

Dipeptidyl peptidase 4. Chain: a, b. Fragment: unp residues 31-766. Synonym: dipeptidyl peptidase iv, dpp iv, t-cell activation antigen cd26, tp103, adenosine deaminase complexing protein 2, adabp. Engineered: yes

Source:

Homo sapiens. Organism_taxid: 9606. Gene: dpp4, adcp2, cd26. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.43Å R-factor: 0.246 R-free: 0.295

Authors:

M.J.Ammirati,S.Liu,D.W.Piotrowski

Key ref:

M.J.Ammirati et al. (2009). (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor. Bioorg Med Chem Lett, 19, 1991-1995. PubMed id: 19275964

Date:

13-Nov-08 Release date: 23-Jun-09

Protein chains

P27487  (DPP4_HUMAN) -  Dipeptidyl peptidase 4 from Homo sapiens

Seq: 766 a.a.

Struc: 728 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.14.5 - dipeptidyl-peptidase Iv.
• Reaction: Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, from a polypeptide, preferentially when Xbb is Pro, provided Xcc is neither Pro nor hydroxyproline.

Bioorg Med Chem Lett 19:1991-1995 (2009)

PubMed id: 19275964

(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor.

M.J.Ammirati, K.M.Andrews, D.D.Boyer, A.M.Brodeur, D.E.Danley, S.D.Doran, B.Hulin, S.Liu, R.K.McPherson, S.J.Orena, J.C.Parker, J.Polivkova, X.Qiu, C.B.Soglia, J.L.Treadway, M.A.VanVolkenburg, D.C.Wilder, D.W.Piotrowski.

ABSTRACT

A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.