PDBsum entry 2f2c

Cell cycle/transferase

PDB id: 2f2c

Contents

Protein chains

244 a.a. *

280 a.a. *

Ligands

SO4

AP9

DMS

* Residue conservation analysis

PDB id:

2f2c

Name:

Cell cycle/transferase

Title:

X-ray structure of human cdk6-vcyclinwith the inhibitor aminopurvalanol

Structure:

Cyclin homolog. Chain: a. Synonym: v-cyclin. Engineered: yes. Cell division protein kinase 6. Chain: b. Fragment: fragment 1-308. Synonym: serine/threonine-protein kinase plstire. Engineered: yes

Source:

Herpesvirus saimiri (strain 11). Organism_taxid: 10383. Strain: 11. Gene: 72, eclf2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Homo sapiens. Human. Organism_taxid: 9606.

Biol. unit:

Dimer (from PQS)

Resolution:

2.80Å R-factor: 0.241 R-free: 0.301

Authors:

U.Schulze-Gahmen,H.Lu

Key ref:

H.Lu and U.Schulze-Gahmen (2006). Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition. J Med Chem, 49, 3826-3831. PubMed id: 16789739 DOI: 10.1021/jm0600388

Date:

16-Nov-05 Release date: 13-Jun-06

Protein chain

Q01043  (CGH2_SHV21) -  Cyclin homolog from Saimiriine herpesvirus 2 (strain 11)

Seq: 254 a.a.

Struc: 244 a.a.

Protein chain

Q00534  (CDK6_HUMAN) -  Cyclin-dependent kinase 6 from Homo sapiens

Seq: 326 a.a.

Struc: 280 a.a.

Enzyme reactions

• Enzyme class 1: Chain A: E.C.?
• Enzyme class 2: Chain B: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm0600388

J Med Chem 49:3826-3831 (2006)

PubMed id: 16789739

Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition.

H.Lu, U.Schulze-Gahmen.

ABSTRACT

Cyclin-dependent kinases (CDKs) are key players in cell cycle control, and genetic alterations of CDKs and their regulators have been linked to a variety of cancers. Hence, CDKs are obvious targets for therapeutic intervention in various proliferative diseases, including cancer. To date, drug design efforts have mostly focused on CDK2 because methods for crystallization of its inhibitor complexes have been well established. CDK4 and CDK6, however, may be at least as important as enzymes for cell cycle regulation and could provide alternative treatment options. We describe here two complex structures of human CDK6 with a very specific kinase inhibitor, PD0332991, which is based on a pyrido[2,3-d]pyrimidin-7-one scaffold, and with the less specific aminopurvalanol inhibitor. Analysis of the structures suggests that relatively small conformational differences between CDK2 and CDK6 in the hinge region are contributing to the inhibitor specificity by inducing changes in the inhibitor orientation that lead to sterical clashes in CDK2 but not CDK6. These complex structures provide valuable insights for the future development of CDK-specific inhibitors.