6u6a: Difference between revisions

Latest revision as of 07:44, 11 October 2023

Crystal structure of Yck2 from Candida albicans in complex with kinase inhibitor GW461484A

Structural highlights

6u6a is a 1 chain structure with sequence from Candida albicans SC5314. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.45Å
Ligands:	Q0J, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A0A1D8PKB4_CANAL

Publication Abstract from PubMed

New strategies are urgently needed to counter the threat to human health posed by drug-resistant fungi. To explore an as-yet unexploited target space for antifungals, we screened a library of protein kinase inhibitors for the ability to reverse resistance of the most common human fungal pathogen, Candida albicans, to caspofungin, a widely used antifungal. This screen identified multiple 2,3-aryl-pyrazolopyridine scaffold compounds capable of restoring caspofungin sensitivity. Using chemical genomic, biochemical, and structural approaches, we established the target for our most potent compound as Yck2, a casein kinase 1 family member. Combination of this compound with caspofungin eradicated drug-resistant C. albicans infection while sparing co-cultured human cells. In mice, genetic depletion of YCK2 caused an approximately 3-log10 decline in fungal burden in a model of systemic caspofungin-resistant C. albicans infection. Structural insights and our tool compound's profile in culture support targeting the Yck2 kinase function as a broadly active antifungal strategy.

Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2.,Caplan T, Lorente-Macias A, Stogios PJ, Evdokimova E, Hyde S, Wellington MA, Liston S, Iyer KR, Puumala E, Shekhar-Guturja T, Robbins N, Savchenko A, Krysan DJ, Whitesell L, Zuercher WJ, Cowen LE Cell Chem Biol. 2020 Mar 19;27(3):269-282.e5. doi:, 10.1016/j.chembiol.2019.12.008. Epub 2020 Jan 7. PMID:31924499^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Caplan T, Lorente-Macias A, Stogios PJ, Evdokimova E, Hyde S, Wellington MA, Liston S, Iyer KR, Puumala E, Shekhar-Guturja T, Robbins N, Savchenko A, Krysan DJ, Whitesell L, Zuercher WJ, Cowen LE. Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2. Cell Chem Biol. 2020 Mar 19;27(3):269-282.e5. doi:, 10.1016/j.chembiol.2019.12.008. Epub 2020 Jan 7. PMID:31924499 doi:https://dx.doi.org/10.1016/j.chembiol.2019.12.008

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OCA

[1] Caplan T, Lorente-Macias A, Stogios PJ, Evdokimova E, Hyde S, Wellington MA, Liston S, Iyer KR, Puumala E, Shekhar-Guturja T, Robbins N, Savchenko A, Krysan DJ, Whitesell L, Zuercher WJ, Cowen LE. Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2. Cell Chem Biol. 2020 Mar 19;27(3):269-282.e5. doi:, 10.1016/j.chembiol.2019.12.008. Epub 2020 Jan 7. PMID:31924499 doi:https://dx.doi.org/10.1016/j.chembiol.2019.12.008

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='6u6a' size='340' side='right'caption='[[6u6a]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6u6a]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Canal Canal]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U6A OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6U6A FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6u6a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_albicans_SC5314 Candida albicans SC5314]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U6A FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q0J:2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine'>Q0J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.45&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6u69|6u69]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q0J:2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine'>Q0J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">YCK2, orf19.7001, CAALFM_C305650WA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=237561 CANAL])</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=6u6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u6a OCA], [https://pdbe.org/6u6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u6a RCSB], [https://www.ebi.ac.uk/pdbsum/6u6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u6a ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6u6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u6a OCA], [http://pdbe.org/6u6a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u6a RCSB], [http://www.ebi.ac.uk/pdbsum/6u6a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u6a ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/A0A1D8PKB4_CANAL A0A1D8PKB4_CANAL]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Canal]]
+[[Category: Candida albicans SC5314]]
 [[Category: Large Structures]]
-[[Category: Structural genomic]]
+[[Category: Chang C]]
-[[Category: Chang, C]]
+[[Category: Di Leo R]]
-[[Category: Evdokimova, E]]
+[[Category: Evdokimova E]]
-[[Category: Joachimiak, A]]
+[[Category: Joachimiak A]]
-[[Category: Leo, R Di]]
+[[Category: Satchell KJF]]
-[[Category: Satchell, K J.F]]
+[[Category: Savchenko A]]
-[[Category: Savchenko, A]]
+[[Category: Stogios PJ]]
-[[Category: Stogios, P J]]
-[[Category: Casein kinase 1]]
-[[Category: Kinase]]
-[[Category: Kinase inhibitor]]
-[[Category: National institute of allergy and infectious disease]]
-[[Category: Niaid]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]
-[[Category: Yck2]]

6u6a: Difference between revisions

Latest revision as of 07:44, 11 October 2023

Crystal structure of Yck2 from Candida albicans in complex with kinase inhibitor GW461484A

Structural highlights

Function

Publication Abstract from PubMed

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References

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