PDBsum entry 4cfx

Cell cycle

PDB id: 4cfx

Contents

Protein chains

299 a.a.

260 a.a.

Ligands

G6T ×2

Waters ×88

PDB id:

4cfx

Name:

Cell cycle

Title:

Structure-based design of c8-substituted o6-cyclohexylmethoxyguanine cdk1 and 2 inhibitors.

Structure:

Cyclin-dependent kinase 2. Chain: a, c. Synonym: cell division protein kinase 2, p33 protein kinase. Engineered: yes. Other_details: phosphorylated on residue t160. Cyclin-a2. Chain: b, d. Fragment: cdk-activating fragment, residues 173-432. Synonym: cyclin-a.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli b. Expression_system_taxid: 37762.

Resolution:

3.50Å R-factor: 0.208 R-free: 0.269

Authors:

B.Carbain,D.J.Paterson,E.Anscombe,A.Campbell,C.Cano,A.Echalier, J.Endicott,B.T.Golding,K.Haggerty,I.R.Hardcastle,P.Jewsbury, D.R.Newell,M.E.M.Noble,C.Roche,L.Z.Wang,R.Griffin

Key ref:

B.Carbain et al. (2014). 8-Substituted O(6)-cyclohexylmethylguanine CDK2 inhibitors: using structure-based inhibitor design to optimize an alternative binding mode. J Med Chem, 57, 56-70. PubMed id: 24304238 DOI: 10.1021/jm401555v

Date:

19-Nov-13 Release date: 10-Dec-14

Protein chains

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 299 a.a.*

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 260 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, C: 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⁺

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

reference

DOI no: 10.1021/jm401555v

J Med Chem 57:56-70 (2014)

PubMed id: 24304238

8-Substituted O(6)-cyclohexylmethylguanine CDK2 inhibitors: using structure-based inhibitor design to optimize an alternative binding mode.

B.Carbain, D.J.Paterson, E.Anscombe, A.J.Campbell, C.Cano, A.Echalier, J.A.Endicott, B.T.Golding, K.Haggerty, I.R.Hardcastle, P.J.Jewsbury, D.R.Newell, M.E.Noble, C.Roche, L.Z.Wang, R.J.Griffin.

ABSTRACT

Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.