3NGA

Human CK2 catalytic domain in complex with CX-4945

PDB DOI: https://doi.org/10.2210/pdb3NGA/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2010-06-11 Released: 2010-12-15
Deposition Author(s): Ferguson, A.D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.71 ?
R-Value Free: 0.218
R-Value Work: 0.188
R-Value Observed: 0.189

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Structural basis of CX-4945 binding to human protein kinase CK2.

Ferguson, A.D., Sheth, P.R., Basso, A.D., Paliwal, S., Gray, K., Fischmann, T.O., Le, H.V.

(2011) FEBS Lett 585: 104-110

PubMed: 21093442 Search on PubMed
DOI: https://doi.org/10.1016/j.febslet.2010.11.019
Primary Citation of Related Structures:
3NGA, 3NSZ

PubMed Abstract:
Protein kinase CK2 (CK2), a constitutively active serine/threonine kinase, is involved in a variety of roles essential to the maintenance of cellular homeostasis. Elevated levels of CK2 expression results in the dysregulation of key signaling pathways that regulate transcription, and has been implicated in cancer. The adenosine-5'-triphosphate-competitive inhibitor CX-4945 has been reported to show broad spectrum anti-proliferative activity in multiple cancer cell lines. Although the enzymatic IC(50) of CX-4945 has been reported, the thermodynamics and structural basis of binding to CK2α remained elusive. Presented here are the crystal structures of human CK2α in complex with CX-4945 and adenylyl phosphoramidate at 2.7 and 1.3 ?, respectively. Biophysical analysis of CX-4945 binding is also described. This data provides the structural rationale for the design of more potent inhibitors against this emerging cancer target.

Organizational Affiliation

Drug Design Department, Merck Research Laboratory, Kenilworth, NJ 07033, USA. andrew.ferguson@astrazeneca.com

Macromolecule Content

Total Structure Weight: 81.13 kDa
Atom Count: 5,794
Modelled Residue Count: 662
Deposited Residue Count: 666
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Casein kinase II subunit alpha	A, B	333	Homo sapiens	Mutation(s): 0 Gene Names: CK2, CK2A1, CSNK2A1 EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P68400 (Homo sapiens) Explore P68400 Go to UniProtKB: P68400
PHAROS: P68400 GTEx: ENSG00000101266
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P68400
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
3NG Query on 3NG 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]	5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid C₁₉ H₁₂ Cl N₃ O₂ MUOKSQABCJCOPU-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]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B]	D [auth A] E [auth A] F [auth A] G [auth A] I [auth B] D [auth A], E [auth A], F [auth A], G [auth A], I [auth B], J [auth B], K [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
3NG	BindingDB: 3NGA	Ki: min: 0.22, max: 0.38 (nM) from 3 assay(s)
		Kd: min: 0.38, max: 0.56 (nM) from 3 assay(s)
		IC50: min: 0.3, max: 2000 (nM) from 23 assay(s)
		EC50: min: 1000, max: 5300 (nM) from 2 assay(s)
	PDBBind: 3NGA	Kd: 10 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.71 ?
R-Value Free: 0.218
R-Value Work: 0.188
R-Value Observed: 0.189
Space Group: P 4₃ 2₁ 2

Unit Cell:

Length ( ? )	Angle ( ? )
a = 127.64	α = 90
b = 127.64	β = 90
c = 125.75	γ = 90

Software Package:

Software Name	Purpose
CrystalClear	data collection
MOLREP	phasing
BUSTER	refinement
XDS	data reduction
SCALA	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2010-12-15

Deposition Author(s):

Ferguson, A.D.

Revision History (Full details and data files)

Version 1.0: 2010-12-15
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2024-02-21
Changes: Data collection, Database references, Derived calculations