3SXF

Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with Bumped Kinase Inhibitor, RM-1-89

3SXF の概要

• エントリーDOI: 10.2210/pdb3sxf/pdb
• 関連するPDBエントリー: 3I79 3I7B 3I7C 3MWU 3N51 3NCG 3NYV 3SX9 3T3U 3T3V
• 分子名称: Calmodulin-domain protein kinase 1, 3-(6-ethoxynaphthalen-2-yl)-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: serine/threonine protein kinase, transferase, calcium-binding, atp-binding, calmodulin, ef hand, bumped kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Toxoplasma gondii
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55714.53

構造登録者

Larson, E.T.,Merritt, E.A. (登録日: 2011-07-14, 公開日: 2012-03-14, 最終更新日: 2023-09-13)

主引用文献

Larson, E.T.,Ojo, K.K.,Murphy, R.C.,Johnson, S.M.,Zhang, Z.,Kim, J.E.,Leibly, D.J.,Fox, A.M.,Reid, M.C.,Dale, E.J.,Perera, B.G.,Kim, J.,Hewitt, S.N.,Hol, W.G.,Verlinde, C.L.,Fan, E.,Van Voorhis, W.C.,Maly, D.J.,Merritt, E.A.
Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1.
J.Med.Chem., 55:2803-2810, 2012

PubMed Abstract: Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC.

PubMed: 22369268
DOI: 10.1021/jm201725v

実験手法

X-RAY DIFFRACTION (2.04 Å)