PDBsum entry 1dm2

Cell cycle

PDB id: 1dm2

Contents

Protein chain

274 a.a. *

Ligands

HMD

EDO ×4

Waters ×85

* Residue conservation analysis

PDB id:

1dm2

Name:

Cell cycle

Title:

Human cyclin-dependent kinase 2 complexed with the inhibitor hymenialdisine

Structure:

Cyclin-dependent kinase 2. Chain: a. Synonym: cell division protein kinase 2, p33 protein kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: sf9 cells. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.10Å R-factor: 0.192 R-free: 0.267

Authors:

A.M.Thunnissen,S.-H.Kim

Key ref:

L.Meijer et al. (2000). Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. Chem Biol, 7, 51-63. PubMed id: 10662688 DOI: 10.1016/S1074-5521(00)00063-6

Date:

13-Dec-99 Release date: 31-May-00

Protein chain

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

Seq: 298 a.a.

Struc: 274 a.a.

Enzyme reactions

• Enzyme class: 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/S1074-5521(00)00063-6

Chem Biol 7:51-63 (2000)

PubMed id: 10662688

Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.

L.Meijer, A.M.Thunnissen, A.W.White, M.Garnier, M.Nikolic, L.H.Tsai, J.Walter, K.E.Cleverley, P.C.Salinas, Y.Z.Wu, J.Biernat, E.M.Mandelkow, S.H.Kim, G.R.Pettit.

ABSTRACT

BACKGROUND: Over 2000 protein kinases regulate cellular functions. Screening for inhibitors of some of these kinases has already yielded some potent and selective compounds with promising potential for the treatment of human diseases. RESULTS: The marine sponge constituent hymenialdisine is a potent inhibitor of cyclin-dependent kinases, glycogen synthase kinase-3beta and casein kinase 1. Hymenialdisine competes with ATP for binding to these kinases. A CDK2-hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83 residues of CDK2, as observed with other inhibitors. Hymenialdisine inhibits CDK5/p35 in vivo as demonstrated by the lack of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical neurons, and also inhibits GSK-3 in vivo as shown by the inhibition of MAP-1B phosphorylation. Hymenialdisine also blocks the in vivo phosphorylation of the microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3 and CDK5/p35 in Alzheimer's disease (cross-reacting with Alzheimer's-specific AT100 antibodies). CONCLUSIONS: The natural product hymenialdisine is a new kinase inhibitor with promising potential applications for treating neurodegenerative disorders.

Selected figure(s)

Figure 2.
Figure 2. Inhibition of CDK1/cyclin B by HD analogues. CDK1/cyclin B was assayed as described in the Supplementary material section. Activity is presented as% of maximal activity (i.e. in the absence of inhibitors).

Figure 8.
Figure 8. Protein–inhibitor interactions in the CDK2–HD complex. (a) Stereo diagram showing the refined structure of HD in the ATP-binding pocket of CDK2. Inferred hydrogen bonds are shown as thin dotted lines. Oxygen atoms are shown in red, nitrogen atoms in blue and bromine in green. (b) Schematic illustration of the interactions between CDK2 and HD. Protein sidechain contacts are indicated by lines connecting to the respective residue box, whereas interactions with mainchain atoms are shown as lines to the specific mainchain atom. Van der Waals contacts are indicated by dotted lines and hydrogen bonds by broken lines.

The above figures are reprinted by permission from Cell Press: Chem Biol (2000, 7, 51-63) copyright 2000.

Figures were selected by an automated process.