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| | ==Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1268== | | ==Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1268== |
| - | <StructureSection load='4jbv' size='340' side='right' caption='[[4jbv]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='4jbv' size='340' side='right'caption='[[4jbv]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4jbv]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxgo Toxgo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JBV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JBV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4jbv]] 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=4JBV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JBV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=V68:1-[(1-METHYLPIPERIDIN-4-YL)METHYL]-3-[6-(2-METHYLPROPOXY)NAPHTHALEN-2-YL]PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINE'>V68</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3t3v|3t3v]], [[3sxf|3sxf]], [[3sx9|3sx9]], [[3v51|3v51]], [[3upz|3upz]], [[3upx|3upx]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V68:1-[(1-METHYLPIPERIDIN-4-YL)METHYL]-3-[6-(2-METHYLPROPOXY)NAPHTHALEN-2-YL]PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINE'>V68</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AAG53993, CDPK1, TGGT1_059880, TGVEG_042030 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5811 TOXGO])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4jbv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jbv OCA], [https://pdbe.org/4jbv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jbv RCSB], [https://www.ebi.ac.uk/pdbsum/4jbv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jbv ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Calcium/calmodulin-dependent_protein_kinase Calcium/calmodulin-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.17 2.7.11.17] </span></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=4jbv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jbv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jbv RCSB], [http://www.ebi.ac.uk/pdbsum/4jbv PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/Q9BJF5_TOXGO Q9BJF5_TOXGO] |
| - | 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.
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| - | Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes.,Vidadala RS, Ojo KK, Johnson SM, Zhang Z, Leonard SE, Mitra A, Choi R, Reid MC, Keyloun KR, Fox AM, Kennedy M, Silver-Brace T, Hume JC, Kappe S, Verlinde CL, Fan E, Merritt EA, Van Voorhis WC, Maly DJ Eur J Med Chem. 2014 Mar 3;74:562-73. doi: 10.1016/j.ejmech.2013.12.048. Epub, 2014 Jan 11. PMID:24531197<ref>PMID:24531197</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | == References ==
| + | |
| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Calcium/calmodulin-dependent protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Toxgo]] | + | [[Category: Toxoplasma gondii]] |
| - | [[Category: Larson, E T]] | + | [[Category: Larson ET]] |
| - | [[Category: Merritt, E A]] | + | [[Category: Merritt EA]] |
| - | [[Category: Atp-binding]]
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| - | [[Category: Bumped kinase inhibitor]]
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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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| - | [[Category: Transferase-transferase inhibitor complex]]
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