2IEI

Crystal structure of rabbit muscle glycogen phosphorylase in complex with 3,4-dihydro-2-quinolone

PDB DOI: https://doi.org/10.2210/pdb2IEI/pdb

Classification: TRANSFERASE
Organism(s): Oryctolagus cuniculus
Mutation(s): No

Deposited: 2006-09-19 Released: 2006-12-26
Deposition Author(s): Birch, A.M., Kenny, P.W., Oikonomakos, N.G., Otterbein, L., Schofield, P., Whittamore, P.R.O., Whalley, D.P., Rowsell, S., Pauptit, R., Pannifer, A., Breed, J., Minshull, C.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.91 Å
R-Value Free: 0.297
R-Value Work: 0.255
R-Value Observed: 0.257

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Development of potent, orally active 1-substituted-3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors.

Birch, A.M., Kenny, P.W., Oikonomakos, N.G., Otterbein, L., Schofield, P., Whittamore, P.R., Whalley, D.P.

(2007) Bioorg Med Chem Lett 17: 394-399

PubMed: 17095214 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2006.10.037
Primary Citation of Related Structures:
2IEG, 2IEI

PubMed Abstract:
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site.

Organizational Affiliation

AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. [email protected]

Macromolecule Content

Total Structure Weight: 195.94 kDa
Atom Count: 13,536
Modelled Residue Count: 1,590
Deposited Residue Count: 1,684
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Glycogen phosphorylase, muscle form	A, B	842	Oryctolagus cuniculus	Mutation(s): 0 EC: 2.4.1.1
UniProt
Find proteins for P00489 (Oryctolagus cuniculus) Explore P00489 Go to UniProtKB: P00489
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00489
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FRX Query on FRX Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain F [auth B] MOL2 format, chain D [auth A] MOL2 format, chain F [auth B] mmCIF format, chain D [auth A] mmCIF format, chain F [auth B]	D [auth A], F [auth B]	(S)-2-CHLORO-N-(1-(2-(2-HYDROXYETHYLAMINO)-2-OXOETHYL)-2-OXO-1,2,3,4-TETRAHYDROQUINOLIN-3-YL)-6H-THIENO[2,3-B]PYRROLE-5-CARBOXAMIDE C₂₀ H₁₉ Cl N₄ O₄ S VUKPNWLGSLOHIF-AWEZNQCLSA-N		Interactions Focus chain D [auth A] Focus chain F [auth B] Interactions & Density Focus chain D [auth A] Focus chain F [auth B]
PLR Query on PLR Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain E [auth B] MOL2 format, chain C [auth A] MOL2 format, chain E [auth B] mmCIF format, chain C [auth A] mmCIF format, chain E [auth B]	C [auth A], E [auth B]	(5-HYDROXY-4,6-DIMETHYLPYRIDIN-3-YL)METHYL DIHYDROGEN PHOSPHATE C₈ H₁₂ N O₅ P RBCOYOYDYNXAFA-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain E [auth B] Interactions & Density Focus chain C [auth A] Focus chain E [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.91 Å
R-Value Free: 0.297
R-Value Work: 0.255
R-Value Observed: 0.257
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 114.402	α = 90
b = 125.344	β = 90
c = 129.309	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
ADSC	data collection
MOSFLM	data reduction
CCP4	data scaling
AMoRE	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2006-12-26

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2006-12-26
Type: Initial release
Version 1.1: 2008-05-01
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Version format compliance
Version 1.3: 2024-11-20
Changes: Data collection, Database references, Derived calculations, Structure summary