4URK

PI3Kg in complex with AZD6482

PDB DOI: https://doi.org/10.2210/pdb4URK/pdb

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

Deposited: 2014-06-30 Released: 2014-10-22
Deposition Author(s): Giordanetto, F., Barlaam, B., Berglund, S., Edman, K., Karlsson, O., Lindberg, J., Nylander, S., Inghardt, T.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.90 Å
R-Value Free: 0.309
R-Value Work: 0.250
R-Value Observed: 0.254

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Discovery of 9-(1-Phenoxyethyl)-2-Morpholino-4-Oxo-Pyrido[1, 2-A]Pyrimidine-7-Carboxamides as Oral Pi3Kbeta Inhibitors, Useful as Antiplatelet Agents.

Giordanetto, F., Barlaam, B., Berglund, S., Edman, K., Karlsson, O., Lindberg, J., Nylander, S., Inghardt, T.

(2014) Bioorg Med Chem Lett 24: 3936

PubMed: 25042253 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2014.07.007
Primary Citation of Related Structures:
4URK

PubMed Abstract:
Optimization of AZD6482 (2), the first antiplatelet PI3Kβ inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kα to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3Kβ inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance.

Organizational Affiliation

Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: [email protected].

Macromolecule Content

Total Structure Weight: 111.14 kDa
Atom Count: 6,823
Modelled Residue Count: 837
Deposited Residue Count: 966
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM	A	966	Homo sapiens	Mutation(s): 0 EC: 2.7.1.153 (PDB Primary Data), 2.7.11.1 (PDB Primary Data), 2.7.1.137 (UniProt), 2.7.1.154 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P48736 (Homo sapiens) Explore P48736 Go to UniProtKB: P48736
PHAROS: P48736 GTEx: ENSG00000105851
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P48736
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A82 Query on A82 Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	2-[[(1R)-1-(7-methyl-2-morpholin-4-yl-4-oxidanylidene-pyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoic acid C₂₂ H₂₄ N₄ O₄ IRTDIKMSKMREGO-OAHLLOKOSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
A82	BindingDB: 4URK	IC50: min: 870, max: 1090 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.90 Å
R-Value Free: 0.309
R-Value Work: 0.250
R-Value Observed: 0.254
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 143.179	α = 90
b = 67.521	β = 95.71
c = 106.167	γ = 90

Software Package:

Software Name	Purpose
BUSTER	refinement
MOSFLM	data reduction
SCALA	data scaling
MOLREP	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-10-22

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-10-22
Type: Initial release
Version 1.1: 2024-01-10
Changes: Data collection, Database references, Derived calculations, Other, Refinement description