PDBsum entry 4jbv

Transferase/transferase inhibitor

PDB id: 4jbv

Contents

Protein chain

458 a.a.

Ligands

V68

Waters ×104

PDB id:

4jbv

Name:

Transferase/transferase inhibitor

Title:

Calcium-dependent protein kinase 1 from toxoplasma gondii (tgcdpk1) in complex with inhibitor uw1268

Structure:

Calmodulin-domain protein kinase 1. Chain: a. Synonym: calmodulin-domain protein kinase, putative. Engineered: yes

Source:

Toxoplasma gondii. Organism_taxid: 5811. Gene: aag53993, cdpk1, tggt1_059880, tgveg_042030. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.95Å R-factor: 0.200 R-free: 0.239

Authors:

E.A.Merritt,E.T.Larson

Key ref:

R.S.Vidadala et al. (2014). Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes. Eur J Med Chem, 74, 562-573. PubMed id: 24531197 DOI: 10.1016/j.ejmech.2013.12.048

Date:

20-Feb-13 Release date: 19-Mar-14

Protein chain

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

Seq: 507 a.a.

Struc: 458 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

DOI no: 10.1016/j.ejmech.2013.12.048

Eur J Med Chem 74:562-573 (2014)

PubMed id: 24531197

Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes.

R.S.Vidadala, K.K.Ojo, S.M.Johnson, Z.Zhang, S.E.Leonard, A.Mitra, R.Choi, M.C.Reid, K.R.Keyloun, A.M.Fox, M.Kennedy, T.Silver-Brace, J.C.Hume, S.Kappe, C.L.Verlinde, E.Fan, E.A.Merritt, W.C.Van Voorhis, D.J.Maly.

ABSTRACT

Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein kinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitoes. We demonstrate that two structural features in the ATP-binding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block Plasmodium falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria.