3VJM | pdb_00003vjm

Crystal structure of human depiptidyl peptidase IV (DPP-4) in complex with a prolylthiazolidine inhibitor #1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 
    0.224 (Depositor), 0.220 (DCC) 
  • R-Value Work: 
    0.185 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 
    0.187 (Depositor) 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted W61Click on this verticalbar to view detailsBest fitted NAGClick on this verticalbar to view details

This is version 2.2 of the entry. See complete history


Literature

Fused bicyclic heteroarylpiperazine-substituted l-prolylthiazolidines as highly potent DPP-4 inhibitors lacking the electrophilic nitrile group

Yoshida, T.Akahoshi, F.Sakashita, H.Sonda, S.Takeuchi, M.Tanaka, Y.Nabeno, M.Kishida, H.Miyaguchi, I.Hayashi, Y.

(2012) Bioorg Med Chem 20: 5033-5041

  • DOI: https://doi.org/10.1016/j.bmc.2012.06.033
  • Primary Citation of Related Structures:  
    3VJM

  • PubMed Abstract: 

    Hypoglycemic agents with a mechanism of depeptidyl peptidase IV (DPP-4) inhibition are suitable for once daily oral dosing. It is difficult to strike a balance between inhibitory activity and duration of action in plasma for inhibitors bearing an electrophilic nitrile group. We explored fused bicyclic heteroarylpiperazine substituted at the γ-position of the proline structure in the investigation of L-prolylthiazolidines lacking the electrophilic nitrile. Among them, 2-trifluoroquinolyl compound 8g is the most potent, long-lasting DPP-4 inhibitor (IC(50) = 0.37 nmol/L) with high selectivity against other related peptidases. X-ray crystal structure determination of 8g indicates that CH-π interactions generated between the quinolyl ring and the guanidinyl group of Arg358 enhances the DPP-4 inhibitory activity and selectivity.


  • Organizational Affiliation

    Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dipeptidyl peptidase 4
A, B
740Homo sapiensMutation(s): 0 
Gene Names: DPP4ADCP2CD26
EC: 3.4.14.5
UniProt & NIH Common Fund Data Resources
Find proteins for P27487 (Homo sapiens)
Explore P27487 
Go to UniProtKB:  P27487
PHAROS:  P27487
GTEx:  ENSG00000197635 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27487
Glycosylation
Glycosylation Sites: 6Go to GlyGen: P27487-1
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C, D, E, F, G
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
W61
Query on W61

Download Ideal Coordinates CCD File 
H [auth A],
M [auth B]
1,3-thiazolidin-3-yl[(2S,4S)-4-{4-[2-(trifluoromethyl)quinolin-4-yl]piperazin-1-yl}pyrrolidin-2-yl]methanone
C22 H26 F3 N5 O S
JWKZKADFQDTDIU-YJBOKZPZSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
I [auth A]
J [auth A]
K [auth A]
L [auth A]
N [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
W61 BindingDB:  3VJM IC50: 0.37 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free:  0.224 (Depositor), 0.220 (DCC) 
  • R-Value Work:  0.185 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 0.187 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 117.946α = 90
b = 125.944β = 90
c = 137.214γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted W61Click on this verticalbar to view detailsBest fitted NAGClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-15
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2023-11-08
    Changes: Data collection, Database references, Refinement description, Structure summary
  • Version 2.2: 2024-10-09
    Changes: Structure summary