3I7C

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

Summary for 3I7C

• Entry DOI: 10.2210/pdb3i7c/pdb
• Related: 3I79 3I7B 3MWU 3N51 3NCG
• Descriptor: Calmodulin-domain protein kinase 1, 1-tert-butyl-3-naphthalen-2-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: 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
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 1
• Total formula weight: 56294.61

Authors

Larson, E.T.,Merritt, E.A.,Medical Structural Genomics of Pathogenic Protozoa (MSGPP) (deposition date: 2009-07-08, release date: 2010-02-09, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.98 Å)