PDBsum entry 1xo2

Cell cycle/transferase

PDB id: 1xo2

Contents

Protein chains

243 a.a. *

289 a.a. *

Ligands

FSE

* Residue conservation analysis

PDB id:

1xo2

Name:

Cell cycle/transferase

Title:

Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin

Structure:

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

Source:

Saimiriine herpesvirus 2. Herpesvirus saimiri. Organism_taxid: 10381. Gene: 72, eclf2. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: sf-9. Homo sapiens. Human.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.90Å R-factor: 0.260 R-free: 0.313

Authors:

H.S.Lu,D.J.Chang,B.Baratte,L.Meijer,U.Schulze-Gahmen

Key ref:

H.Lu et al. (2005). Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J Med Chem, 48, 737-743. PubMed id: 15689157 DOI: 10.1021/jm049353p

Date:

05-Oct-04 Release date: 01-Mar-05

Protein chain

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

Seq: 254 a.a.

Struc: 243 a.a.

Protein chain

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

Seq: 326 a.a.

Struc: 289 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/jm049353p

J Med Chem 48:737-743 (2005)

PubMed id: 15689157

Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin.

H.Lu, D.J.Chang, B.Baratte, L.Meijer, U.Schulze-Gahmen.

ABSTRACT

Cyclin-dependent kinases (CDKs) play a central role in cell cycle control, apoptosis, transcription, and neuronal functions. They are important targets for the design of drugs with antimitotic or antineurodegenerative effects. CDK4 and CDK6 form a subfamily among the CDKs in mammalian cells, as defined by sequence similarities. Compared to CDK2 and CDK5, structural information on CDK4 and CDK6 is sparse. We describe here the crystal structure of human CDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin. Fisetin binds to the active form of CDK6, forming hydrogen bonds with the side chains of residues in the binding pocket that undergo large conformational changes during CDK activation by cyclin binding. The 4-keto group and the 3-hydroxyl group of fisetin are hydrogen bonded with the backbone in the hinge region between the N-terminal and C-terminal kinase domain, as has been observed for many CDK inhibitors. However, CDK2 and HCK kinase in complex with other flavone inhibitors such as quercetin and flavopiridol showed a different binding mode with the inhibitor rotated by about 180 degrees. The structural information of the CDK6-fisetin complex is correlated with the binding affinities of different flavone inhibitors for CDK6. This complex structure is the first description of an inhibitor complex with a kinase from the CDK4/6 subfamily and can provide a basis for selecting and designing inhibitor compounds with higher affinities and specificities.