PDBsum entry 1ol1

Transferase/transferase inhibitor

PDB id: 1ol1

Contents

Protein chains

296 a.a. *

258 a.a. *

Ligands

CIR-CIR-LEU-ILE-PFF-NH2 ×2

Waters ×73

* Residue conservation analysis

PDB id:

1ol1

Name:

Transferase/transferase inhibitor

Title:

Cyclin a binding groove inhibitor h-cit-cit-leu-ile-(p-f-phe)-nh2

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Cyclin a2. Chain: b, d. Fragment: residues 173 - 432. Synonym: cyclin a. Engineered: yes.

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.

Biol. unit:

Trimer (from PDB file)

Resolution:

2.90Å R-factor: 0.209 R-free: 0.284

Authors:

G.Kontopidis,M.Andrews,C.Mcinnes,A.Cowan,H.Powers,L.Innes,A.Plater, G.Griffiths,D.Paterson,D.Zheleva,D.Lane,S.Green,M.Walkinshaw, P.Fischer

Key ref:

G.Kontopidis et al. (2003). Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange. Structure, 11, 1537-1546. PubMed id: 14656438 DOI: 10.1016/j.str.2003.11.006

Date:

04-Aug-03 Release date: 11-Dec-03

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: 10.1016/j.str.2003.11.006

Structure 11:1537-1546 (2003)

PubMed id: 14656438

Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange.

G.Kontopidis, M.J.Andrews, C.McInnes, A.Cowan, H.Powers, L.Innes, A.Plater, G.Griffiths, D.Paterson, D.I.Zheleva, D.P.Lane, S.Green, M.D.Walkinshaw, P.M.Fischer.

ABSTRACT

Inhibition of CDK2/CA (cyclin-dependent kinase 2/cyclin A complex) activity through blocking of the substrate recognition site in the cyclin A subunit has been demonstrated to be an effective method for inducing apoptosis in tumor cells. We have used the cyclin binding motif (CBM) present in the tumor suppressor proteins p21(WAF1) and p27(KIP1) as a template to optimize the minimal sequence necessary for CDK2/CA inhibition. A series of peptides were prepared, containing nonnatural amino acids, which possess nano- to micromolar CDK2-inhibitory activity. Here we present X-ray structures of the protein complex CDK2/CA, together with the cyclin groove-bound peptides H-Ala-Ala-Abu-Arg-Ser-Leu-Ile-(p-F-Phe)-NH(2) (peptide 1), H-Arg-Arg-Leu-Ile-Phe-NH(2) (peptide 2), Ac-Arg-Arg-Leu-Asn-(m-Cl-Phe)-NH(2) (peptide 3), H-Arg-Arg-Leu-Asn-(p-F-Phe)-NH(2) (peptide 4), and H-Cit-Cit-Leu-Ile-(p-F-Phe)-NH(2) (peptide 5). Some of the peptide complexes presented here were obtained through the novel technique of ligand exchange within protein crystals. This method may find general application for obtaining complex structures of proteins with surface-bound ligands.

Selected figure(s)

Figure 3.
Figure 3. The Electron Density Maps of Peptides 1-5The 2F[o] - 1F[c] maps are contoured at a level corresponding to 1.2 s for the peptides bound to the nonoccluded cyclin groove.(A) Superimposition of the structures of peptide 2 in the free (yellow) and partially occluded (green) CBG shows the differences of the two copies of the peptide.(B) Overlay of the bound conformations of peptides 1 (gray), 2 (green), 3 (red), 4 (CPK coloring), and 5 (magenta).

The above figure is reprinted by permission from Cell Press: Structure (2003, 11, 1537-1546) copyright 2003.

Figure was selected by an automated process.