3UQG

c-SRC kinase domain in complex with bumpless BKI analog UW1243

3UQG の概要

• エントリーDOI: 10.2210/pdb3uqg/pdb
• 関連するPDBエントリー: 3UPX 3UPZ 3UQF 3V51 3V5P 3V5T
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• 機能のキーワード: tyrosine protein kinase, atp-binding, kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Gallus gallus (bantam,chickens)
• 細胞内の位置: Cell membrane (By similarity): P00523
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65917.86

構造登録者

Merritt, E.A.,Larson, E.T. (登録日: 2011-11-20, 公開日: 2012-03-14, 最終更新日: 2024-02-28)

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 (2.2 Å)