4BIB

Crystal Structures of Ask1-inhibitor Complexes

PDB DOI: https://doi.org/10.2210/pdb4BIB/pdb

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

Deposited: 2013-04-10 Released: 2013-07-03
Deposition Author(s): Singh, O., Shillings, A., Craggs, P., Wall, I., Rowland, P., Skarzynski, T., Hobbs, C.I., Hardwick, P., Tanner, R., Blunt, M., Witty, D.R., Smith, K.J.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.43 Å
R-Value Free: 0.239
R-Value Work: 0.201
R-Value Observed: 0.203

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Crystal Structures of Ask1-Inhibtor Complexes Provide a Platform for Structure Based Drug Design.

Singh, O., Shillings, A., Craggs, P., Wall, I., Rowland, P., Skarzynski, T., Hobbs, C.I., Hardwick, P., Tanner, R., Blunt, M., Witty, D.R., Smith, K.J.

(2013) Protein Sci 22: 1071

PubMed: 23776076 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/pro.2298
Primary Citation of Related Structures:
4BF2, 4BHN, 4BIB, 4BIC, 4BID, 4BIE

PubMed Abstract:
ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.

Organizational Affiliation

GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.

Macromolecule Content

Total Structure Weight: 72.01 kDa
Atom Count: 4,206
Modelled Residue Count: 512
Deposited Residue Count: 636
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5	A, B	318	Homo sapiens	Mutation(s): 1 EC: 2.7.11.25
UniProt & NIH Common Fund Data Resources
Find proteins for Q99683 (Homo sapiens) Explore Q99683 Go to UniProtKB: Q99683
PHAROS: Q99683 GTEx: ENSG00000197442
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q99683
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
IEO Query on IEO Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain H [auth B] mmCIF format, chain C [auth A] mmCIF format, chain H [auth B]	C [auth A], H [auth B]	3-cyano-4-(piperidin-4-yloxy)-1H-indole-7-carboxamide C₁₅ H₁₆ N₄ O₂ LJQBAOLMNHGSQC-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain H [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain F [auth A] MOL2 format, chain D [auth A] MOL2 format, chain F [auth A] mmCIF format, chain D [auth A] mmCIF format, chain F [auth A]	D [auth A], F [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain F [auth A] Interactions & Density Focus chain D [auth A] Focus chain F [auth A]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth A] SDF format, chain I [auth B] MOL2 format, chain E [auth A] MOL2 format, chain G [auth A] MOL2 format, chain I [auth B] mmCIF format, chain E [auth A] mmCIF format, chain G [auth A] mmCIF format, chain I [auth B]	E [auth A], G [auth A], I [auth B]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain E [auth A] Focus chain G [auth A] Focus chain I [auth B] Interactions & Density Focus chain E [auth A] Focus chain G [auth A] Focus chain I [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
IEO	PDBBind: 4BIB	IC50: 250 (nM) from 1 assay(s)
IEO	BindingDB: 4BIB	IC50: 251 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.43 Å
R-Value Free: 0.239
R-Value Work: 0.201
R-Value Observed: 0.203
Space Group: P 6₅ 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 77.95	α = 90
b = 77.95	β = 90
c = 418.43	γ = 120

Software Package:

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

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-07-03

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2013-07-03
Type: Initial release
Version 1.1: 2013-08-07
Changes: Database references
Version 1.2: 2023-12-20
Changes: Data collection, Database references, Derived calculations, Other, Refinement description