3SWW

Crystal structure of human dpp-iv in complex with sa-(+)-3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyphenyl)- 2-methyl-5h-pyrrolo[3,4-b]pyridin-7(6h)-one

PDB DOI: https://doi.org/10.2210/pdb3SWW/pdb

Classification: HYDROLASE/HYDROLASE inhibitor
Organism(s): Homo sapiens
Expression System: Komagataella pastoris
Mutation(s): No

Deposited: 2011-07-14 Released: 2011-10-26
Deposition Author(s): Klei, H.E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.234
R-Value Work: 0.197
R-Value Observed: 0.199

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.2 of the entry. See complete history.

Literature

7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site.

Wang, W., Devasthale, P., Wang, A., Harrity, T., Egan, D., Morgan, N., Cap, M., Fura, A., Klei, H.E., Kish, K., Weigelt, C., Sun, L., Levesque, P., Li, Y.X., Zahler, R., Kirby, M.S., Hamann, L.G.

(2011) Bioorg Med Chem Lett 21: 6646-6651

PubMed: 21996520 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2011.09.074
Primary Citation of Related Structures:
3SWW, 3SX4

PubMed Abstract:
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice.

Organizational Affiliation

Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA.

Macromolecule Content

Total Structure Weight: 178.72 kDa
Atom Count: 12,465
Modelled Residue Count: 1,454
Deposited Residue Count: 1,506
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dipeptidyl peptidase 4	A, B	753	Homo sapiens	Mutation(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 Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P27487
Glycosylation
Glycosylation Sites: 6	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
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C, D	2		N-Glycosylation	Interactions Focus chain C Focus chain D Interactions & Density Focus chain C Focus chain D
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
KXB Query on KXB Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain P [auth B] MOL2 format, chain J [auth A] MOL2 format, chain P [auth B] mmCIF format, chain J [auth A] mmCIF format, chain P [auth B]	J [auth A], P [auth B]	3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyethyl)-2-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one C₁₈ H₁₉ Cl₂ N₃ O₂ CLNAIMPDNPYUGV-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain P [auth B] Interactions & Density Focus chain J [auth A] Focus chain P [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 K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain O [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 K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain O [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 K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain O [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], K [auth B], L [auth B], M [auth B], N [auth B], O [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 K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [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 K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
KXB	PDBBind: 3SWW	Ki: 4 (nM) from 1 assay(s)
KXB	BindingDB: 3SWW	Ki: 4 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.234
R-Value Work: 0.197
R-Value Observed: 0.199
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 65.534	α = 90
b = 67.928	β = 90
c = 423.472	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
PDB_EXTRACT	data extraction
CBASS	data collection
HKL-2000	data reduction
HKL-2000	data scaling
AMoRE	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2011-10-26

Deposition Author(s):

Klei, H.E.

Revision History (Full details and data files)

Version 1.0: 2011-10-26
Type: Initial release
Version 1.1: 2012-05-23
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
Version 2.1: 2023-09-13
Changes: Data collection, Database references, Refinement description, Structure summary
Version 2.2: 2024-11-06
Changes: Structure summary