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| | ==Calcium-Dependent Protein Kinase 1 from Neospora caninum== | | ==Calcium-Dependent Protein Kinase 1 from Neospora caninum== |
| - | <StructureSection load='4m97' size='340' side='right' caption='[[4m97]], [[Resolution|resolution]] 2.05Å' scene=''> | + | <StructureSection load='4m97' size='340' side='right'caption='[[4m97]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4m97]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Neocl Neocl]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M97 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M97 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4m97]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Neospora_caninum_Liverpool Neospora caninum Liverpool]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M97 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M97 FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDPK1, NCLIV_011980, XP_003880764 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=572307 NEOCL])</td></tr> | + | </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=4m97 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m97 OCA], [https://pdbe.org/4m97 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m97 RCSB], [https://www.ebi.ac.uk/pdbsum/4m97 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m97 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>
| + | |
| - | <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=4m97 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m97 OCA], [http://pdbe.org/4m97 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4m97 RCSB], [http://www.ebi.ac.uk/pdbsum/4m97 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4m97 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/F0V9W9_NEOCL F0V9W9_NEOCL] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Calcium/calmodulin-dependent protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Neocl]] | + | [[Category: Neospora caninum Liverpool]] |
| - | [[Category: Merritt, E A]] | + | [[Category: Merritt EA]] |
| - | [[Category: Atp-binding]]
| + | |
| - | [[Category: Calcium-binding]]
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| - | [[Category: Serine/threonine protein kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
F0V9W9_NEOCL
Publication Abstract from PubMed
Despite the enormous economic importance of Neospora caninum related veterinary diseases, the number of effective therapeutic agents is relatively small. Development of new therapeutic strategies to combat the economic impact of neosporosis remains an important scientific endeavor. This study demonstrates molecular, structural and phenotypic evidence that N. caninum calcium-dependent protein kinase 1 (NcCDPK1) is a promising molecular target for neosporosis drug development. Recombinant NcCDPK1 was expressed, purified and screened against a select group of bumped kinase inhibitors (BKIs) previously shown to have low IC50s against Toxoplasma gondii CDPK1 and T. gondii tachyzoites. NcCDPK1 was inhibited by low concentrations of BKIs. The three-dimensional structure of NcCDPK1 in complex with BKIs was studied crystallographically. The BKI-NcCDPK1 structures demonstrated the structural basis for potency and selectivity. Calcium-dependent conformational changes in solution as characterized by small-angle X-ray scattering are consistent with previous structures in low Calcium-state but different in the Calcium-bound active state than predicted by X-ray crystallography. BKIs effectively inhibited N. caninum tachyzoite proliferation in vitro. Electron microscopic analysis of N. caninum cells revealed ultra-structural changes in the presence of BKI compound 1294. BKI compound 1294 interfered with an early step in Neospora tachyzoite host cell invasion and egress. Prolonged incubation in the presence of 1294 interfered produced observable interference with viability and replication. Oral dosing of BKI compound 1294 at 50 mg/kg for 5 days in established murine neosporosis resulted in a 10-fold reduced cerebral parasite burden compared to untreated control. Further experiments are needed to determine the PK, optimal dosage, and duration for effective treatment in cattle and dogs, but these data demonstrate proof-of-concept for BKIs, and 1294 specifically, for therapy of bovine and canine neosporosis.
Neospora caninum Calcium-Dependent Protein Kinase 1 Is an Effective Drug Target for Neosporosis Therapy.,Ojo KK, Reid MC, Kallur Siddaramaiah L, Muller J, Winzer P, Zhang Z, Keyloun KR, Vidadala RS, Merritt EA, Hol WG, Maly DJ, Fan E, Van Voorhis WC, Hemphill A PLoS One. 2014 Mar 28;9(3):e92929. doi: 10.1371/journal.pone.0092929. eCollection, 2014. PMID:24681759[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ojo KK, Reid MC, Kallur Siddaramaiah L, Muller J, Winzer P, Zhang Z, Keyloun KR, Vidadala RS, Merritt EA, Hol WG, Maly DJ, Fan E, Van Voorhis WC, Hemphill A. Neospora caninum Calcium-Dependent Protein Kinase 1 Is an Effective Drug Target for Neosporosis Therapy. PLoS One. 2014 Mar 28;9(3):e92929. doi: 10.1371/journal.pone.0092929. eCollection, 2014. PMID:24681759 doi:http://dx.doi.org/10.1371/journal.pone.0092929
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