PDBsum entry 3o0g

Transferase/transferase activator

PDB id: 3o0g

Contents

Protein chains

289 a.a. *

149 a.a. *

264 a.a. *

Ligands

3O0

Waters ×234

* Residue conservation analysis

PDB id:

3o0g

Name:

Transferase/transferase activator

Title:

Crystal structure of cdk5:p25 in complex with an atp analogue

Structure:

Cell division protein kinase 5. Chain: a, b. Synonym: cyclin-dependent kinase 5, tau protein kinase ii catalytic subunit, tpkii catalytic subunit, serine/threonine-protein kinase pssalre. Engineered: yes. Cyclin-dependent kinase 5 activator 1. Chain: d, e. Fragment: unp residues 146-293.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk5. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Gene: p25.

Resolution:

1.95Å R-factor: 0.228 R-free: 0.256

Authors:

M.Mapelli

Key ref:

J.S.Ahn et al. (2005). Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation. Chem Biol, 12, 811-823. PubMed id: 16039528

Date:

19-Jul-10 Release date: 26-Jan-11

Protein chain

Q00535  (CDK5_HUMAN) -  Cyclin-dependent kinase 5 from Homo sapiens

Seq: 292 a.a.

Struc: 289 a.a.*

Protein chains

Q15078  (CD5R1_HUMAN) -  Cyclin-dependent kinase 5 activator 1 from Homo sapiens

Seq: 307 a.a.

Struc: 149 a.a.

Protein chain

Q00535  (CDK5_HUMAN) -  Cyclin-dependent kinase 5 from Homo sapiens

Seq: 292 a.a.

Struc: 264 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.7.11.1 - non-specific serine/threonine protein 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

Chem Biol 12:811-823 (2005)

PubMed id: 16039528

Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation.

J.S.Ahn, M.L.Radhakrishnan, M.Mapelli, S.Choi, B.Tidor, G.D.Cuny, A.Musacchio, L.A.Yeh, K.S.Kosik.

ABSTRACT

Cyclin-dependent kinase 5 (Cdk5) is widely viewed as a possible target for a wide variety of neurological disorders. One pathological role attributed to Cdk5 is the abnormal phosphorylation of tau that may lead to the neuronal inclusions known as neurofibrillary tangles. A high through-put screen for inhibitors of Cdk5-mediated phosphorylation of tau resulted in three compounds with distinct mechanisms of action. One compound is competitive with ATP and has a high affinity for the Cdk5 ATP binding pocket. The second compound also competes with ATP, is noncompetitive with tau, and (uniquely among this class of inhibitors) displaces adjacent amino acid residues to make room for the nitrophenyl group. A third compound did not compete with ATP, but did compete with tau at low concentrations of tau. The SAR and charge optimization derived from cocrystals of the two ATP competitors along with cocrystals of three other ATP competitors map out the importance of filling and properly charging different regions of the ATP binding pocket. Taken together, this analysis shows how the structure of Cdk5 constrains the space of potential inhibitors and reveals a pocket unfilled in all of the structures. These leads could be a starting point for structure-based drug design of more potent and selective inhibitors.