2VGP

Crystal structure of Aurora B kinase in complex with a aminothiazole inhibitor

PDB DOI: https://doi.org/10.2210/pdb2VGP/pdb

Classification: TRANSFERASE
Organism(s): Xenopus laevis
Expression System: Escherichia coli BL21
Mutation(s): No

Deposited: 2007-11-15 Released: 2008-02-26
Deposition Author(s): Andersen, C.B., Wan, Y., Chang, J.W., Lee, C., Liu, Y., Sessa, F., Villa, F., Nallan, L., Musacchio, A., Gray, N.S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.70 Å
R-Value Free: 0.243
R-Value Work: 0.206
R-Value Observed: 0.208

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Discovery of Selective Aminothiazole Aurora Kinase Inhibitors

Andersen, C.B., Wan, Y., Chang, J.W., Riggs, B., Lee, C., Liu, Y., Sessa, F., Villa, F., Kwiatkowski, N., Suzuki, M., Nallan, L., Heald, R., Musacchio, A., Gray, N.S.

(2008) ACS Chem Biol 3: 180

PubMed: 18307303 Search on PubMed
DOI: https://doi.org/10.1021/cb700200w
Primary Citation of Related Structures:
2VGP

PubMed Abstract:
Aurora family kinases regulate important events during mitosis including centrosome maturation and separation, mitotic spindle assembly, and chromosome segregation. Misregulation of Aurora kinases due to genetic amplification and protein overexpression results in aneuploidy and may contribute to tumorigenesis. Here we report the discovery of new small molecule aminothiazole inhibitors of Aurora kinases with exceptional kinase selectivity and report a 1.7 A cocrystal structure with the Aurora B:INCENP complex from Xenopus laevis. The compounds recapitulate the hallmarks of Aurora kinase inhibition, including decreased histone H3 serine 10 phosphorylation, failure to complete cytokinesis, and endoreduplication.

Organizational Affiliation

Department of Biological Chemistry, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.

Macromolecule Content

Total Structure Weight: 77.65 kDa
Atom Count: 6,015
Modelled Residue Count: 627
Deposited Residue Count: 654
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
SERINE/THREONINE-PROTEIN KINASE 12-A	A, B	284	Xenopus laevis	Mutation(s): 0 EC: 2.7.11.1
UniProt
Find proteins for Q6DE08 (Xenopus laevis) Explore Q6DE08 Go to UniProtKB: Q6DE08
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q6DE08
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
INNER CENTROMERE PROTEIN A	C, D	43	Xenopus laevis	Mutation(s): 0
UniProt
Find proteins for O13024 (Xenopus laevis) Explore O13024 Go to UniProtKB: O13024
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O13024
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
AD6 Query on AD6 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth B]	E [auth A], F [auth B]	4-[(5-bromo-1,3-thiazol-2-yl)amino]-N-methylbenzamide C₁₁ H₁₀ Br N₃ O S IMMYNZJEOGNQTM-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth B]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
TPO Query on TPO	A, B	L-PEPTIDE LINKING	C₄ H₁₀ N O₆ P		THR

Binding Affinity Annotations
ID	Source	Binding Affinity
AD6	PDBBind: 2VGP	IC50: 140 (nM) from 1 assay(s)
AD6	Binding MOAD: 2VGP	IC50: 577 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.70 Å
R-Value Free: 0.243
R-Value Work: 0.206
R-Value Observed: 0.208
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 45.958	α = 90
b = 67.196	β = 96.67
c = 117.263	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
HKL-2000	data reduction
SCALEPACK	data scaling
MOLREP	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2008-02-26

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2008-02-26
Type: Initial release
Version 1.1: 2011-05-08
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Version format compliance
Version 1.3: 2023-12-13
Changes: Data collection, Database references, Derived calculations, Other, Refinement description