5ISM

Human DPP4 in complex with a novel 5,5,6-tricyclic pyrrolidine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors.

Cox, J.M.Chu, H.D.Kuethe, J.T.Gao, Y.D.Scapin, G.Eiermann, G.He, H.Li, X.Lyons, K.A.Metzger, J.Petrov, A.Wu, J.K.Xu, S.Sinha-Roy, R.Weber, A.E.Biftu, T.

(2016) Bioorg Med Chem Lett 26: 2622-2626

  • DOI: https://doi.org/10.1016/j.bmcl.2016.04.020
  • Primary Citation of Related Structures:  
    5ISM

  • PubMed Abstract: 

    Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.


  • Organizational Affiliation

    Department of Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: jason_cox@merck.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dipeptidyl peptidase 4
A, B
728Homo sapiensMutation(s): 1 
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
Sequence Annotations
Expand
  • 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
C, D, E, F, G, H, I
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6DG
Query on 6DG

Download Ideal Coordinates CCD File 
N [auth A],
P [auth B]
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-8(9H)-yl)oxan-3-amine
C19 H19 F2 N5 O
CEOQJSZJQDMDFU-PZPSRYQVSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
L [auth A],
O [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
M [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6DG Binding MOAD:  5ISM IC50: 0.7 (nM) from 1 assay(s)
BindingDB:  5ISM IC50: 0.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.274α = 90
b = 126.029β = 90
c = 137.273γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
SCALEPACKdata scaling
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-05-11 
  • Deposition Author(s): Scapin, G.

Revision History  (Full details and data files)

  • Version 1.0: 2016-05-11
    Type: Initial release
  • Version 1.1: 2016-05-18
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Structure summary