3I7C

Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with bumped kinase inhibitor NA-PP2

3I7C の概要

• エントリーDOI: 10.2210/pdb3i7c/pdb
• 関連するPDBエントリー: 3I79 3I7B 3MWU 3N51 3NCG
• 分子名称: Calmodulin-domain protein kinase 1, 1-tert-butyl-3-naphthalen-2-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• 機能のキーワード: protein kinase, calmodulin, ef hand, bumped kinase inhibitor, atp-binding, kinase, nucleotide-binding, serine/threonine-protein kinase, structural genomics, medical structural genomics of pathogenic protozoa, msgpp, transferase
• 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: 56294.61

構造登録者

Larson, E.T.,Merritt, E.A.,Medical Structural Genomics of Pathogenic Protozoa (MSGPP) (登録日: 2009-07-08, 公開日: 2010-02-09, 最終更新日: 2023-11-22)

主引用文献

Ojo, K.K.,Larson, E.T.,Keyloun, K.R.,Castaneda, L.J.,Derocher, A.E.,Inampudi, K.K.,Kim, J.E.,Arakaki, T.L.,Murphy, R.C.,Zhang, L.,Napuli, A.J.,Maly, D.J.,Verlinde, C.L.,Buckner, F.S.,Parsons, M.,Hol, W.G.,Merritt, E.A.,Van Voorhis, W.C.
Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors.
Nat.Struct.Mol.Biol., 17:602-607, 2010

PubMed Abstract: New drugs are needed to treat toxoplasmosis. Toxoplasma gondii calcium-dependent protein kinases (TgCDPKs) are attractive targets because they are absent in mammals. We show that TgCDPK1 is inhibited by low nanomolar levels of bumped kinase inhibitors (BKIs), compounds inactive against mammalian kinases. Cocrystal structures of TgCDPK1 with BKIs confirm that the structural basis for selectivity is due to the unique glycine gatekeeper residue in the ATP-binding site. We show that BKIs interfere with an early step in T. gondii infection of human cells in culture. Furthermore, we show that TgCDPK1 is the in vivo target of BKIs because T. gondii expressing a glycine to methionine gatekeeper mutant enzyme show significantly decreased sensitivity to BKIs. Thus, design of selective TgCDPK1 inhibitors with low host toxicity may be achievable.

PubMed: 20436472
DOI: 10.1038/nsmb.1818

実験手法

X-RAY DIFFRACTION (1.98 Å)