4A5S

CRYSTAL STRUCTURE OF HUMAN DPP4 IN COMPLEX WITH A NOVAL HETEROCYCLIC DPP4 INHIBITOR

PDB DOI: https://doi.org/10.2210/pdb4A5S/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2011-10-28 Released: 2012-02-08
Deposition Author(s): Ostermann, N., Kroemer, M., Zink, F., Gerhartz, B., Sutton, J.M., Clark, D.E., Dunsdon, S.J., Fenton, G., Fillmore, A., Harris, N.V., Higgs, C., Hurley, C.A., Krintel, S.L., MacKenzie, R.E., Duttaroy, A., Gangl, E., Maniara, W., Sedrani, R., Namoto, K., Sirockin, F., Trappe, J., Hassiepen, U., Baeschlin, D.K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.62 Å
R-Value Free: 0.179
R-Value Work: 0.164
R-Value Observed: 0.164

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.0 of the entry. See complete history.

Literature

Novel Heterocyclic Dpp-4 Inhibitors for the Treatment of Type 2 Diabetes.

Sutton, J.M., Clark, D.E., Dunsdon, S.J., Fenton, G., Fillmore, A., Harris, N.V., Higgs, C., Hurley, C.A., Krintel, S.L., Mackenzie, R.E., Duttaroy, A., Gangl, E., Maniara, W., Sedrani, R., Namoto, K., Ostermann, N., Gerhartz, B., Sirockin, F., Trappe, J., Hassiepen, U., Baeschlin, D.K.

(2012) Bioorg Med Chem Lett 22: 1464

PubMed: 22177783 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2011.11.054
Primary Citation of Related Structures:
4A5S

PubMed Abstract:
Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.

Organizational Affiliation

Argenta Discovery 2009 Ltd, Harlow CM19 5TR, UK. [email protected]

Macromolecule Content

Total Structure Weight: 176.78 kDa
Atom Count: 13,990
Modelled Residue Count: 1,462
Deposited Residue Count: 1,480
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
DIPEPTIDYL PEPTIDASE 4 SOLUBLE FORM	A, B	740	Homo sapiens	Mutation(s): 0 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 Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P27487
Glycosylation
Glycosylation Sites: 7	Glycosylation Focus chain A Focus chain B	Go to GlyGen: P27487-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C	5		N-Glycosylation	Interactions Focus chain C Interactions & Density Focus chain C
Glycosylation Resources
GlyTouCan: G21381MC GlyCosmos: G21381MC GlyGen: G21381MC

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
N7F Query on N7F Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain N [auth B] MOL2 format, chain D [auth A] MOL2 format, chain N [auth B] mmCIF format, chain D [auth A] mmCIF format, chain N [auth B]	D [auth A], N [auth B]	6-[(3S)-3-AMINOPIPERIDIN-1-YL]-5-BENZYL-4-OXO-3-(QUINOLIN-4-YLMETHYL)-4,5-DIHYDRO-3H-PYRROLO[3,2-D]PYRIMIDINE-7-CARBONITRILE C₂₉ H₂₇ N₇ O WRJSBPQWADEDBH-QFIPXVFZSA-N		Interactions Focus chain D [auth A] Focus chain N [auth B] Interactions & Density Focus chain D [auth A] Focus chain N [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] SDF format, chain V [auth B] SDF format, chain W [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] MOL2 format, chain V [auth B] MOL2 format, chain W [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B] mmCIF format, chain V [auth B] mmCIF format, chain W [auth B]	E [auth A] F [auth A] G [auth A] H [auth A] I [auth A] E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], R [auth B], S [auth B], T [auth B], U [auth B], V [auth B], W [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B]	K [auth A] L [auth A] M [auth A] O [auth B] P [auth B] K [auth A], L [auth A], M [auth A], O [auth B], P [auth B], Q [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Interactions & Density Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
N7F	BindingDB: 4A5S	IC50: 17 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.62 Å
R-Value Free: 0.179
R-Value Work: 0.164
R-Value Observed: 0.164
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 97.183	α = 90
b = 121.424	β = 90
c = 190.699	γ = 90

Software Package:

Software Name	Purpose
BUSTER	refinement
XDS	data reduction
XSCALE	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-02-08

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2012-02-08
Type: Initial release
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Other, Structure summary