5KBY

Crystal structure of dipeptidyl peptidase IV in complex with SYR-472

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history. 


Literature

Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism.

Grimshaw, C.E., Jennings, A., Kamran, R., Ueno, H., Nishigaki, N., Kosaka, T., Tani, A., Sano, H., Kinugawa, Y., Koumura, E., Shi, L., Takeuchi, K.

(2016) PLoS One 11: e0157509-e0157509

  • DOI: https://doi.org/10.1371/journal.pone.0157509
  • Primary Citation of Related Structures:  
    5KBY

  • PubMed Abstract: 

    Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4- and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation ≈ 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

    • Organizational Affiliation: 

    Enzymology and Biophysical Chemistry, Takeda California, Inc., San Diego, California, United States of America.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dipeptidyl peptidase 4
A, B, C, D
740Homo sapiensMutation(s): 0 
Gene Names: DPP4, ADCP2, CD26
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
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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
E, F, G, H, I
E, F, G, H, I, J
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6RL
Query on 6RL
Download Ideal Coordinates CCD File 
CA [auth D],
N [auth A],
T [auth B],
X [auth C]		2-[[6-[(3~{R})-3-azanylpiperidin-1-yl]-3-methyl-2,4-bis(oxidanylidene)pyrimidin-1-yl]methyl]-4-fluoranyl-benzenecarboni trile
C18 H20 F N5 O2
IWYJYHUNXVAVAA-OAHLLOKOSA-N
NAG
Query on NAG
Download Ideal Coordinates CCD File 
AA [auth D]
BA [auth D]
K [auth A]
L [auth A]
M [auth A]
AA [auth D],
BA [auth D],
K [auth A],
L [auth A],
M [auth A],
O [auth B],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
U [auth C],
V [auth C],
W [auth C],
Y [auth D],
Z [auth D]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6RL BindingDB:  5KBY Ki: 5.1 (nM) from 1 assay(s)
IC50: min: 1.3, max: 4 (nM) from 3 assay(s)
Binding MOAD:  5KBY Ki: 1.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.573α = 90
b = 122.165β = 114.57
c = 143.704γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-13
    Type: Initial release
  • Version 1.1: 2016-09-07
    Changes: Non-polymer description
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-09-27
    Changes: Data collection, Database references, Refinement description, Structure summary