PDBsum entry 2ajc

Hydrolase/hydrolase inhibitor

PDB id: 2ajc

Contents

Protein chains

728 a.a. *

Ligands

NAG-NAG ×7

NAG-NAG-BMA ×2

NAG ×15

SO4 ×4

AES ×4

Waters ×1496

* Residue conservation analysis

PDB id:

2ajc

Name:

Hydrolase/hydrolase inhibitor

Title:

Porcine dipeptidyl peptidase iv (cd26) in complex with 4-(2- aminoethyl)-benzene sulphonyl fluoride (aebsf)

Structure:

Dipeptidyl peptidase 4. Chain: a, b, c, d. Fragment: extracellular domain. Synonym: dipeptidyl peptidase iv, dpp iv, t-cell activation antigen cd26, tp103, adenosine deaminase complexing protein-2, adabp. Ec: 3.4.14.5

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Organ: kidney

Biol. unit:

Dimer (from PQS)

Resolution:

1.95Å R-factor: 0.202 R-free: 0.234

Authors:

M.Engel,T.Hoffmann,S.Manhart,U.Heiser,S.Chambre,R.Huber,H.U.Demuth, W.Bode

Key ref:

M.Engel et al. (2006). Rigidity and flexibility of dipeptidyl peptidase IV: crystal structures of and docking experiments with DPIV. J Mol Biol, 355, 768-783. PubMed id: 16330047 DOI: 10.1016/j.jmb.2005.11.014

Date:

01-Aug-05 Release date: 28-Feb-06

Protein chains

P22411  (DPP4_PIG) -  Dipeptidyl peptidase 4 from Sus scrofa

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.

DOI no: 10.1016/j.jmb.2005.11.014

J Mol Biol 355:768-783 (2006)

PubMed id: 16330047

Rigidity and flexibility of dipeptidyl peptidase IV: crystal structures of and docking experiments with DPIV.

M.Engel, T.Hoffmann, S.Manhart, U.Heiser, S.Chambre, R.Huber, H.U.Demuth, W.Bode.

ABSTRACT

Dipeptidyl peptidase IV (DPIV) is an alpha,beta-hydrolase-like serine exopeptidase, which removes dipeptides, preferentially with a C-terminal l-Pro residue, from the N terminus of longer peptide substrates. Previously, we determined the tetrameric 1.8A crystal structure of native porcine DPIV. Each monomer is composed of a beta-propeller and a catalytic domain, which together embrace an internal cavity housing the active centre. This cavity is connected to the bulk solvent by a "propeller opening" and a "side opening". Here, we analyse DPIV complexes with a t-butyl-Gly-Pro-Ile tripeptide, Pro-boroPro, a piperazine purine compound, and aminoethyl phenyl sulfonylfluoride. The latter two compounds bind to the active-site groove in a compact and a quite bulky manner, respectively, causing considerable shifts of the catalytic Ser630 side-chain and of the Tyr547 phenolic group, which forms the oxyanion hole. The tripeptide, mimicking a peptide substrate, is clamped to the active site through tight interactions via its N-terminal alpha-ammonium group, the P2 carbonyl group, the P1-l-Pro side-chain, the C-terminal carboxylate group, and the stable orthoacid ester amide formed between the scissile peptide carbonyl group and Ser630 O(gamma). This stable trapping of the tripeptide could be due to stabilization of the protonated His740 imidazolium cation by the adjacent negatively charged C-terminal carboxylate group, preventing proton transfer to the leaving group nitrogen atom. Docking experiments with the compact rigid 58 residue protein aprotinin, which had been shown to be processed by DPIV, indicate that the Arg1-Pro2 N terminus can access the DPIV active site only upon widening of its side openings, probably by separation of the first and the last propeller blades, and/or of the catalytic and the propeller domain.

Selected figure(s)

Figure 4.
Figure 4. Covalent and non-covalent binding of inhibitors (green, carbon; red, oxygen; and blue, nitrogen) towards the DPIV active site (active residues, light blue; enzyme residues, beige). Intermolecular hydrogen bonds are given as broken black lines, the 2F[obs] -F[calc] electron density omit maps (blue mesh, contoured at 1s) are given for the inhibitor alone. The Figure was prepared using the program PYMOL (http://pymol.sourceforge.net/). (a) Ball-and-stick representation of l-Pro-l-boroPro in complex with DPIV. (b) Ball-and-stick representation of 7-benzyl-1,3-dimethyl-8-piperazin-1-yl-3,7-dihydro-purine-2,6-dione (BDPX) shown against the solid surface of the DPIV residues around the active site. (c) Ball-and-stick representation of BDPX against the DPIV active site.

Figure 5.
Figure 5. Covalent binding of the 4-(2-aminoethyl)-benzene sulphonyl fluoride inhibitor (AEBSF, ball-and-stick representation: green, carbon; red, oxygen; and blue, nitrogen) towards the active site of DPIV. The Figures was were prepared using the program PYMOL (http://pymol.sourceforge.net/). (a) Surface representation of the DPIV residues around the active site. (b) Ball-and-stick representation of the DPIV residues (in light blue) and around the active site (beige). Intermolecular hydrogen bonds are given as broken black lines, the 2F[obs] -F[calc] electron density omit map (blue mesh, contoured at 1s) is given for the inhibitor and the Tyr547 phenolic group of DPIV.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 355, 768-783) copyright 2006.

Figures were selected by an automated process.