4AF3

Human Aurora B Kinase in complex with INCENP and VX-680

PDB DOI: https://doi.org/10.2210/pdb4AF3/pdb

Classification: TRANSFERASE/INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2012-01-16 Released: 2012-04-11
Deposition Author(s): Elkins, J.M., Vollmar, M., Wang, J., Picaud, S., Arrowsmith, C.H., Edwards, A., Bountra, C., von Delft, F., Knapp, S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.75 Å
R-Value Free: 0.264
R-Value Work: 0.205
R-Value Observed: 0.208

Starting Model: experimental
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Ligand Structure Quality Assessment

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

Literature

Crystal Structure of Human Aurora B in Complex with Incenp and Vx-680.

Elkins, J.M., Santaguida, S., Musacchio, A., Knapp, S.

(2012) J Med Chem 55: 7841

PubMed: 22920039 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/jm3008954
Primary Citation of Related Structures:
4AF3

PubMed Abstract:
We present the structure of the human Aurora B kinase domain in complex with the C-terminal Aurora-binding region of human INCENP and the Aurora kinase inhibitor VX-680. The structure unexpectedly reveals a dimeric arrangement of the Aurora B:INCENP complex, which was confirmed to exist in solution by analytical ultracentrifugation. The dimerization involves a domain swap of the activation loop, resulting in a different conformation of the DFG motif as compared to that seen in other kinase complexes with VX-680. The binding of INCENP differs significantly from that seen in the Xenopus laevis Aurora B:INCENP complex currently used as a model for structure-based design for this important oncology target.

Organizational Affiliation

Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom. [email protected]

Macromolecule Content

Total Structure Weight: 42.4 kDa
Atom Count: 2,427
Modelled Residue Count: 296
Deposited Residue Count: 363
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
AURORA KINASE B	A	292	Homo sapiens	Mutation(s): 1 EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q96GD4 (Homo sapiens) Explore Q96GD4 Go to UniProtKB: Q96GD4
PHAROS: Q96GD4 GTEx: ENSG00000178999
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q96GD4
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
INNER CENTROMERE PROTEIN	B [auth D]	71	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NQS7 (Homo sapiens) Explore Q9NQS7 Go to UniProtKB: Q9NQS7
PHAROS: Q9NQS7 GTEx: ENSG00000149503
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9NQS7
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
VX6 Query on VX6 Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE C₂₃ H₂₈ N₈ O S GCIKSSRWRFVXBI-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
VX6	BindingDB: 4AF3	Ki: min: 1.8, max: 18 (nM) from 2 assay(s)
		Kd: min: 7, max: 7.4 (nM) from 2 assay(s)
		IC50: min: 17, max: 55 (nM) from 7 assay(s)
	PDBBind: 4AF3	IC50: 31 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.75 Å
R-Value Free: 0.264
R-Value Work: 0.205
R-Value Observed: 0.208
Space Group: P 3₁ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 80.145	α = 90
b = 80.145	β = 90
c = 92.542	γ = 120

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
Aimless	data scaling
SAWAYA	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-04-11

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2012-04-11
Type: Initial release
Version 1.1: 2012-09-26
Changes: Database references, Structure summary
Version 1.2: 2018-01-24
Changes: Structure summary
Version 1.3: 2023-12-20
Changes: Data collection, Database references, Derived calculations, Other, Refinement description