PDBsum entry 5ehh

Hydrolase

PDB id: 5ehh

Contents

Protein chain

724 a.a.

Ligands

TYR-PRO-PHE-PHE-NH2

Metals

_MG ×2

_ZN

__K

Waters ×270

PDB id:

5ehh

Name:

Hydrolase

Title:

Structure of human dpp3 in complex with endomorphin-2.

Structure:

Dipeptidyl peptidase 3. Chain: a. Fragment: unp residues 1-726. Synonym: dipeptidyl aminopeptidase iii,dipeptidyl arylamidase iii, dipeptidyl peptidase iii,dpp iii,enkephalinase b. Engineered: yes. Mutation: yes. Endomorphin-2. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dpp3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: ril. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.38Å R-factor: 0.196 R-free: 0.237

Authors:

P.Kumar,V.Reithofer,M.Reisinger,T.Pavkov-Keller,S.Wallner, P.Macheroux,K.Gruber

Key ref:

P.Kumar et al. (2016). Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition. Sci Rep, 6, 23787. PubMed id: 27025154 DOI: 10.1038/srep23787

Date:

28-Oct-15 Release date: 13-Apr-16

Protein chain

P27915  (POLG_DEN3P) -  Genome polyprotein from Dengue virus type 3 (strain Philippines/H87/1956)

Seq: 3390 a.a.

Struc: 724 a.a.*

* PDB and UniProt seqs differ at 651 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.14.4 - dipeptidyl-peptidase Iii.
• Reaction: Release of an N-terminal dipeptide from a peptide comprising four or more residues, with broad specificity. Also acts on dipeptidyl 2-naphthylamides.

DOI no: 10.1038/srep23787

Sci Rep 6:23787 (2016)

PubMed id: 27025154

Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition.

P.Kumar, V.Reithofer, M.Reisinger, S.Wallner, T.Pavkov-Keller, P.Macheroux, K.Gruber.

ABSTRACT

Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is likely involved in a number of physiological processes such as nociception and is also implicated in several forms of cancer. We present high-resolution crystal structures of hDPP III in complex with opioid peptides (Met-and Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide inhibitor IVYPW. These structures confirm the previously reported large conformational change of the enzyme upon ligand binding and show that the structure of the closed conformation is independent of the nature of the bound peptide. The overall peptide-binding mode is also conserved ensuring the correct positioning of the scissile peptide bond with respect to the catalytic zinc ion. The structure of the angiotensin-II complex shows, how longer peptides are accommodated in the binding cleft of hDPP III. Differences in the binding modes allow a distinction between real substrates and inhibitory peptides or "slow" substrates. The latter displace a zinc bound water molecule necessitating the energetically much less favoured anhydride mechanism as opposed to the favoured promoted-water mechanism. The structural data also form the necessary framework for the design of specific hDPP III inhibitors.