5EHH

Structure of human DPP3 in complex with endomorphin-2.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

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

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

(2016) Sci Rep 6: 23787-23787

  • DOI: https://doi.org/10.1038/srep23787
  • Primary Citation of Related Structures:  
    5E2Q, 5E33, 5E3A, 5E3C, 5EGY, 5EHH

  • PubMed 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.


  • Organizational Affiliation

    Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50/3, 8010 Graz, Austria.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dipeptidyl peptidase 3726Homo sapiensMutation(s): 6 
Gene Names: DPP3
EC: 3.4.14.4
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NY33 (Homo sapiens)
Explore Q9NY33 
Go to UniProtKB:  Q9NY33
PHAROS:  Q9NY33
GTEx:  ENSG00000254986 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NY33
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Endomorphin-25Homo sapiensMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.035α = 90
b = 105.457β = 93.49
c = 64.719γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHENIXphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Austrian Science FundAustriaW901

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-13
    Type: Initial release
  • Version 1.1: 2017-09-06
    Changes: Author supporting evidence
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description