PDBsum entry 3i7c

Transferase

PDB id: 3i7c

Contents

Protein chain

462 a.a. *

Ligands

BK2

Waters ×170

* Residue conservation analysis

PDB id:

3i7c

Name:

Transferase

Title:

Calcium-dependent protein kinase 1 from toxoplasma gondii (tgcdpk1) in complex with bumped kinase inhibitor na-pp2

Structure:

Calmodulin-domain protein kinase 1. Chain: a. Fragment: residues 30-507. Engineered: yes

Source:

Toxoplasma gondii. Organism_taxid: 5811. Gene: cdpk1, tgcdpk1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.98Å R-factor: 0.195 R-free: 0.245

Authors:

E.T.Larson,E.A.Merritt,Medical Structural Genomics Of Pathogenic Protozoa (Msgpp)

Key ref:

K.K.Ojo et al. (2010). Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors. Nat Struct Biol, 17, 602-607. PubMed id: 20436472

Date:

08-Jul-09 Release date: 09-Feb-10

Protein chain

Q9BJF5  (Q9BJF5_TOXGO) -  Calmodulin-domain protein kinase 1 from Toxoplasma gondii

Seq: 507 a.a.

Struc: 462 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.17 - calcium/calmodulin-dependent protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Cofactor: Ca(2+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Nat Struct Biol 17:602-607 (2010)

PubMed id: 20436472

Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors.

K.K.Ojo, E.T.Larson, K.R.Keyloun, L.J.Castaneda, A.E.Derocher, K.K.Inampudi, J.E.Kim, T.L.Arakaki, R.C.Murphy, L.Zhang, A.J.Napuli, D.J.Maly, C.L.Verlinde, F.S.Buckner, M.Parsons, W.G.Hol, E.A.Merritt, W.C.Van Voorhis.

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.