2IIV | pdb_00002iiv

Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor

PDB DOI: https://doi.org/10.2210/pdb2IIV/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): Yes

Deposited: 2006-09-28 Released: 2006-11-28
Deposition Author(s): Scapin, G., Weber, A.E., Biftu, T.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.15 Å
R-Value Free:
0.229 (Depositor), 0.220 (DCC)
R-Value Work:
0.194 (Depositor), 0.180 (DCC)
R-Value Observed:
0.197 (Depositor)

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.3 of the entry. See complete history.

Literature

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Biftu, T., Feng, D., Qian, X., Liang, G.B., Kieczykowski, G., Eiermann, G., He, H., Leiting, B., Lyons, K., Petrov, A., Sinha-Roy, R., Zhang, B., Scapin, G., Patel, S., Gao, Y.D., Singh, S., Wu, J., Zhang, X., Thornberry, N.A., Weber, A.E.

(2007) Bioorg Med Chem Lett 17: 49-52

PubMed: 17055272 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2006.09.099
Primary Citation of Related Structures:
2IIT, 2IIV

PubMed Abstract:
Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.

Organizational Affiliation

Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Tesfaye_Biftu@merck.com

Macromolecule Content

Total Structure Weight: 174.57 kDa
Atom Count: 13,220
Modelled Residue Count: 1,456
Deposited Residue Count: 1,456
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	728	Homo sapiens	Mutation(s): 1 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: 7	Glycosylation Focus chain A Focus chain B	Go to GlyGen: P27487-1
Sequence Annotations Expand
Reference Sequence LOADING

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, E, F, G C, D, E, F, G, H, I, J, K	2		N-Glycosylation	Interactions Focus chain C Focus chain D Focus chain E Focus chain F Focus chain G Focus chain H Focus chain I Focus chain J Focus chain K Interactions & Density Focus chain C Focus chain D Focus chain E Focus chain F Focus chain G Focus chain H Focus chain I Focus chain J Focus chain K
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
565 Query on 565 Download Ideal Coordinates CCD File SDF format, chain N [auth A] SDF format, chain R [auth B] MOL2 format, chain N [auth A] MOL2 format, chain R [auth B] mmCIF format, chain N [auth A] mmCIF format, chain R [auth B]	N [auth A], R [auth B]	(3R)-4-[(3R)-3-AMINO-4-(2,4,5-TRIFLUOROPHENYL)BUTANOYL]-3-METHYL-1,4-DIAZEPAN-2-ONE C₁₆ H₂₀ F₃ N₃ O₂ SWKGZJAAGSVROJ-MWLCHTKSSA-N		Interactions Focus chain N [auth A] Focus chain R [auth B] Interactions & Density Focus chain N [auth A] Focus chain R [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain M [auth A] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain L [auth A] SDF format, chain O [auth B] MOL2 format, chain M [auth A] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain L [auth A] MOL2 format, chain O [auth B] mmCIF format, chain M [auth A] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain L [auth A] mmCIF format, chain O [auth B]	L [auth A], M [auth A], O [auth B], P [auth B], Q [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions 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 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
565	BindingDB: 2IIV	IC50: 6.6 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.15 Å
R-Value Free: 0.229 (Depositor), 0.220 (DCC)
R-Value Work: 0.194 (Depositor), 0.180 (DCC)
R-Value Observed: 0.197 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 118.192	α = 90
b = 125.777	β = 90
c = 136.902	γ = 90

Software Package:

Software Name	Purpose
CNS	refinement
PDB_EXTRACT	data extraction
MAR345	data collection
HKL-2000	data reduction
SCALEPACK	data scaling
CNX	phasing
CNX	refinement

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2006-11-28

Deposition Author(s):

Scapin, G.

Weber, A.E.

Biftu, T.

Revision History (Full details and data files)

Version 1.0: 2006-11-28
Type: Initial release
Version 1.1: 2008-05-01
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Non-polymer description, Version format compliance
Version 1.3: 2017-10-18
Changes: Refinement 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: 2021-10-20
Changes: Database references, Structure summary
Version 2.2: 2023-08-30
Changes: Data collection, Refinement description
Version 2.3: 2024-10-30
Changes: Structure summary