2GBF

rat dpp-IV with alkynyl cyanopyrrolidine #1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.250 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Crystal Structures of DPP-IV (CD26) from Rat Kidney Exhibit Flexible Accommodation of Peptidase-Selective Inhibitors.

Longenecker, K.L.Stewart, K.D.Madar, D.J.Jakob, C.G.Fry, E.H.Wilk, S.Lin, C.W.Ballaron, S.J.Stashko, M.A.Lubben, T.H.Yong, H.Pireh, D.Pei, Z.Basha, F.Wiedeman, P.E.Von Geldern, T.W.Trevillyan, J.M.Stoll, V.S.

(2006) Biochemistry 45: 7474-7482

  • DOI: https://doi.org/10.1021/bi060184f
  • Primary Citation of Related Structures:  
    2GBC, 2GBF, 2GBG, 2GBI

  • PubMed Abstract: 

    Dipeptidyl peptidase IV (DPP-IV) belongs to a family of serine peptidases, and due to its indirect regulatory role in plasma glucose modulation, DPP-IV has become an attractive pharmaceutical target for diabetes therapy. DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide. To elucidate the details of the active site for structure-based drug design, we crystallized a natural source preparation of DPP-IV isolated from rat kidney and determined its three-dimensional structure using X-ray diffraction techniques. With a high degree of similarity to structures of human DPP-IV, the active site architecture provides important details for the design of inhibitory compounds, and structures of inhibitor-protein complexes offer detailed insight into three-dimensional structure-activity relationships that include a conformational change of Tyr548. Such accommodation is exemplified by the response to chemical substitution on 2-cyanopyrrolidine inhibitors at the 5 position, which conveys inhibitory selectivity for DPP-IV over closely related homologues. A similar conformational change is also observed in the complex with an unrelated synthetic inhibitor containing a xanthine core that is also selective for DPP-IV. These results suggest the conformational flexibility of Tyr548 is unique among protein family members and may be utilized in drug design to achieve peptidase selectivity.


  • Organizational Affiliation

    Department of Structural Biology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. Kenton.Longenecker@Abbott.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dipeptidyl peptidase 4
A, B
730Rattus norvegicusMutation(s): 0 
EC: 3.4.14.5
UniProt
Find proteins for P14740 (Rattus norvegicus)
Explore P14740 
Go to UniProtKB:  P14740
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP14740
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AIA
Query on AIA

Download Ideal Coordinates CCD File 
C [auth A](1S)-2-[(2S,5R)-2-(AMINOMETHYL)-5-ETHYNYLPYRROLIDIN-1-YL]-1-CYCLOPENTYL-2-OXOETHANAMINE
C14 H23 N3 O
XYVMJMYCUZCIPB-AVGNSLFASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AIA PDBBind:  2GBF Ki: 12 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.250 
  • Space Group: P 21 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 208.171α = 90
b = 208.171β = 90
c = 208.171γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-07-04
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Refinement description