3TNW

Structure of CDK2/cyclin A in complex with CAN508

PDB DOI: https://doi.org/10.2210/pdb3TNW/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens, Bos taurus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2011-09-02 Released: 2012-02-15
Deposition Author(s): Baumli, S., Hole, A.J., Endicott, J.A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.227
R-Value Work: 0.186
R-Value Observed: 0.188

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

The CDK9 C-helix Exhibits Conformational Plasticity That May Explain the Selectivity of CAN508.

Baumli, S., Hole, A.J., Noble, M.E., Endicott, J.A.

(2012) ACS Chem Biol 7: 811-816

PubMed: 22292676 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/cb2004516
Primary Citation of Related Structures:
3TN8, 3TNH, 3TNI, 3TNW

PubMed Abstract:
CDK9 is the kinase of positive transcription elongation factor b and facilitates the transition of paused RNA polymerase II to processive transcription elongation. CDK9 is a validated target for the treatment of cancer, cardiac hypertrophy, and human immunodeficiency virus. Here we analyze different CDK9/cyclin T variants to identify a form of the complex amenable to use in inhibitor design. To demonstrate the utility of this system, we have determined the crystal structures of CDK9/cyclin T and CDK2/cyclin A bound to the CDK9-specific inhibitor CAN508. Comparison of the structures reveals CDK9-specific conformational changes and identifies a CDK9-specific hydrophobic pocket, adjacent to the αC-helix. By comparison with a previously published structure of CDK9/cyclin T/human immunodeficiency virus TAT we find that the CDK9 αC-helix has a degree of conformational variability that has the potential to be exploited for inhibitor design.

Organizational Affiliation

Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K. sonja.baumli@ncl.ac.uk

Macromolecule Content

Total Structure Weight: 128.92 kDa
Atom Count: 9,888
Modelled Residue Count: 1,100
Deposited Residue Count: 1,124
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Cyclin-dependent kinase 2	A, C	300	Homo sapiens	Mutation(s): 0 Gene Names: CDK2 EC: 2.7.11.22
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens) Explore P24941 Go to UniProtKB: P24941
PHAROS: P24941 GTEx: ENSG00000123374
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P24941
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Cyclin-A2	B, D	262	Bos taurus	Mutation(s): 0 Gene Names: CCNA, CCNA2
UniProt
Find proteins for P30274 (Bos taurus) Explore P30274 Go to UniProtKB: P30274
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P30274
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
F18 Query on F18 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth C] MOL2 format, chain E [auth A] MOL2 format, chain F [auth C]	E [auth A], F [auth C]	4-[(E)-(3,5-DIAMINO-1H-PYRAZOL-4-YL)DIAZENYL]PHENOL C₉ H₁₀ N₆ O AYZRKFOEZQBUEA-SEYXRHQNSA-N		Interactions Focus chain E [auth A] Focus chain F [auth C] Interactions & Density Focus chain E [auth A] Focus chain F [auth C]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain G [auth D] SDF format, chain H [auth D] MOL2 format, chain G [auth D] MOL2 format, chain H [auth D]	G [auth D], H [auth D]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain G [auth D] Focus chain H [auth D] Interactions & Density Focus chain G [auth D] Focus chain H [auth D]

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

Binding Affinity Annotations
ID	Source	Binding Affinity
F18	BindingDB: 3TNW	Ki: 6.90e+4 (nM) from 1 assay(s)
F18	BindingDB: 3TNW	IC50: min: 2.00e+4, max: 6.90e+4 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.227
R-Value Work: 0.186
R-Value Observed: 0.188
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 74.05	α = 90
b = 134.57	β = 90
c = 148.28	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
PDB_EXTRACT	data extraction
ADSC	data collection
MOSFLM	data reduction
SCALA	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-02-15

Deposition Author(s):

Baumli, S.

Hole, A.J.

Endicott, J.A.

Revision History (Full details and data files)

Version 1.0: 2012-02-15
Type: Initial release
Version 1.1: 2012-05-30
Changes: Database references
Version 1.2: 2023-09-13
Changes: Data collection, Database references, Derived calculations, Refinement description