3O0G

Crystal Structure of Cdk5:p25 in complex with an ATP analogue

3O0G の概要

• エントリーDOI: 10.2210/pdb3o0g/pdb
• 関連するPDBエントリー: 3O0S
• 分子名称: Cell division protein kinase 5, Cyclin-dependent kinase 5 activator 1, {4-amino-2-[(4-chlorophenyl)amino]-1,3-thiazol-5-yl}(3-nitrophenyl)methanone, ... (4 entities in total)
• 機能のキーワード: kinase, kinase activator complex, kinase inhibitor complex, transferase-transferase activator complex, transferase/transferase activator
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 101507.46

構造登録者

Mapelli, M. (登録日: 2010-07-19, 公開日: 2011-01-26, 最終更新日: 2023-09-06)

主引用文献

Ahn, J.S.,Radhakrishnan, M.L.,Mapelli, M.,Choi, S.,Tidor, B.,Cuny, G.D.,Musacchio, A.,Yeh, L.,Kosik, S.K.
Defining Cdk5 ligand chemical space with small molecule inhibitors of Tau phosphorylation
Chem.Biol., 12:811-823, 2005

PubMed 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.

PubMed: 16039528
DOI: 10.1016/j.chembiol.2005.05.011

実験手法

X-RAY DIFFRACTION (1.95 Å)