PDBsum entry 2uue

Transferase/inhibitor

PDB id: 2uue

Contents

Protein chains

296 a.a. *

258 a.a. *

Ligands

ARG-LEU-ILE-PFF-NH2 ×2

MTZ ×2

GVC ×2

Waters ×244

* Residue conservation analysis

PDB id:

2uue

Name:

Transferase/inhibitor

Title:

Replace: a strategy for iterative design of cyclin binding groove inhibitors

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Other_details: triazol-1-methyl-pyrimidin inhibitor. Cyclin a2. Chain: b, d. Fragment: residues 174-432. Synonym: cyclin a.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct.

Resolution:

2.06Å R-factor: 0.197 R-free: 0.244

Authors:

M.J.Andrews,G.Kontopidis,C.Mcinnes,A.Plater,L.Innes,A.Cowan, P.Jewsbury,P.M.Fischer

Key ref:

M.J.Andrews et al. (2006). REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors. Chembiochem, 7, 1909-1915. PubMed id: 17051658 DOI: 10.1002/cbic.200600189

Date:

02-Mar-07 Release date: 27-Mar-07

Supersedes:

2c5t

Protein chains

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

Seq: 298 a.a.

Struc: 296 a.a.

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 258 a.a.

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: 10.1002/cbic.200600189

Chembiochem 7:1909-1915 (2006)

PubMed id: 17051658

REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors.

M.J.Andrews, G.Kontopidis, C.McInnes, A.Plater, L.Innes, A.Cowan, P.Jewsbury, P.M.Fischer.

ABSTRACT

We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.