6EOQ

DPP9 - Apo


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.334 
  • R-Value Work: 0.273 
  • R-Value Observed: 0.276 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer.

Ross, B.Krapp, S.Augustin, M.Kierfersauer, R.Arciniega, M.Geiss-Friedlander, R.Huber, R.

(2018) Proc Natl Acad Sci U S A 115: E1437-E1445

  • DOI: https://doi.org/10.1073/pnas.1717565115
  • Primary Citation of Related Structures:  
    6EOO, 6EOP, 6EOQ, 6EOR, 6EOS, 6EOT

  • PubMed Abstract: 

    Dipeptidyl peptidases 8 and 9 are intracellular N-terminal dipeptidyl peptidases (preferentially postproline) associated with pathophysiological roles in immune response and cancer biology. While the DPP family member DPP4 is extensively characterized in molecular terms as a validated therapeutic target of type II diabetes, experimental 3D structures and ligand-/substrate-binding modes of DPP8 and DPP9 have not been reported. In this study we describe crystal and molecular structures of human DPP8 (2.5 Å) and DPP9 (3.0 Å) unliganded and complexed with a noncanonical substrate and a small molecule inhibitor, respectively. Similar to DPP4, DPP8 and DPP9 molecules consist of one β-propeller and α/β hydrolase domain, forming a functional homodimer. However, they differ extensively in the ligand binding site structure. In intriguing contrast to DPP4, where liganded and unliganded forms are closely similar, ligand binding to DPP8/9 induces an extensive rearrangement at the active site through a disorder-order transition of a 26-residue loop segment, which partially folds into an α-helix (R-helix), including R160/133, a key residue for substrate binding. As vestiges of this helix are also seen in one of the copies of the unliganded form, conformational selection may contributes to ligand binding. Molecular dynamics simulations support increased flexibility of the R-helix in the unliganded state. Consistently, enzyme kinetics assays reveal a cooperative allosteric mechanism. DPP8 and DPP9 are closely similar and display few opportunities for targeted ligand design. However, extensive differences from DPP4 provide multiple cues for specific inhibitor design and development of the DPP family members as therapeutic targets or antitargets.


  • Organizational Affiliation

    Max Planck Institut für Biochemie, D-82152 Martinsried, Germany; ross@biochem.mpg.de huber@biochem.mpg.de.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dipeptidyl peptidase 9
A, B, C, D
869Homo sapiensMutation(s): 0 
Gene Names: DPP9DPRP2
EC: 3.4.14.5
UniProt & NIH Common Fund Data Resources
Find proteins for Q86TI2 (Homo sapiens)
Explore Q86TI2 
Go to UniProtKB:  Q86TI2
PHAROS:  Q86TI2
GTEx:  ENSG00000142002 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86TI2
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.334 
  • R-Value Work: 0.273 
  • R-Value Observed: 0.276 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.37α = 90
b = 118.02β = 105.49
c = 164.46γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-07
    Type: Initial release
  • Version 1.1: 2018-02-14
    Changes: Database references
  • Version 1.2: 2018-02-28
    Changes: Database references
  • Version 1.3: 2019-10-16
    Changes: Data collection
  • Version 1.4: 2024-01-17
    Changes: Data collection, Database references, Refinement description