4tzr

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==Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1561==
==Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1561==
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<StructureSection load='4tzr' size='340' side='right' caption='[[4tzr]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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<StructureSection load='4tzr' size='340' side='right'caption='[[4tzr]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4tzr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TZR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TZR FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4tzr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TZR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TZR FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UW2:1-{4-AMINO-3-[2-(CYCLOPROPYLOXY)QUINOLIN-6-YL]-1H-PYRAZOLO[3,4-D]PYRIMIDIN-1-YL}-2-METHYLPROPAN-2-OL'>UW2</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4tzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tzr OCA], [http://pdbe.org/4tzr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tzr RCSB], [http://www.ebi.ac.uk/pdbsum/4tzr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tzr ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UW2:1-{4-AMINO-3-[2-(CYCLOPROPYLOXY)QUINOLIN-6-YL]-1H-PYRAZOLO[3,4-D]PYRIMIDIN-1-YL}-2-METHYLPROPAN-2-OL'>UW2</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tzr OCA], [https://pdbe.org/4tzr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tzr RCSB], [https://www.ebi.ac.uk/pdbsum/4tzr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tzr ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/Q9BJF5_TOXGO Q9BJF5_TOXGO]
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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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 homologs 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 modi fi cation 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.
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New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by &gt;85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.
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Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1.,Larson ET, Ojo KK, Murphy RC, Johnson SM, Zhang Z, Kim JE, Leibly DJ, Fox AM, Reid MC, Dale EJ, Perera BG, Kim J, Hewitt SN, Hol WG, Verlinde CL, Fan E, Van Voorhis WC, Maly DJ, Merritt EA J Med Chem. 2012 Feb 27. PMID:22369268<ref>PMID:22369268</ref>
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Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.,Vidadala RS, Rivas KL, Ojo KK, Hulverson MA, Zambriski JA, Bruzual I, Schultz TL, Huang W, Zhang Z, Scheele S, DeRocher AE, Choi R, Barrett LK, Siddaramaiah LK, Hol WG, Fan E, Merritt EA, Parsons M, Freiberg G, Marsh K, Kempf DJ, Carruthers VB, Isoherranen N, Doggett JS, Van Voorhis WC, Maly DJ J Med Chem. 2016 Jul 14;59(13):6531-46. doi: 10.1021/acs.jmedchem.6b00760. Epub, 2016 Jul 1. PMID:27309760<ref>PMID:27309760</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Merritt, E A]]
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[[Category: Large Structures]]
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[[Category: Atp-binding]]
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[[Category: Toxoplasma gondii]]
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[[Category: Bumped kinase inhibitor]]
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[[Category: Merritt EA]]
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[[Category: Calcium-binding]]
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[[Category: Serine/threonine protein kinase]]
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[[Category: Transferase]]
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Current revision

Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1561

PDB ID 4tzr

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