PIF - pocket as a target for C. albicans Pkh selective inhibitors
The phosphoinositide-dependent protein kinase 1, PDK1, is a master kinase that phosphorylates the activation loop of up to 23 AGC kinases. S. cerevisiae has three PDK1 orthologues, Pkh1-3, which also phosphorylate AGC kinases [e.g., Ypk, Tpk, Pkc1, and Sch9]. Pkh1 and 2 are redundant proteins involv...
| Otros Autores: | , , , , , , , , , |
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| Formato: | Artículo |
| Lenguaje: | Inglés |
| Materias: | |
| Acceso en línea: | http://ri.agro.uba.ar/files/intranet/articulo/2013pastorflores.pdf LINK AL EDITOR |
| Aporte de: | Registro referencial: Solicitar el recurso aquí |
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| 245 | 1 | 0 | |a PIF - pocket as a target for C. albicans Pkh selective inhibitors |
| 520 | |a The phosphoinositide-dependent protein kinase 1, PDK1, is a master kinase that phosphorylates the activation loop of up to 23 AGC kinases. S. cerevisiae has three PDK1 orthologues, Pkh1-3, which also phosphorylate AGC kinases [e.g., Ypk, Tpk, Pkc1, and Sch9]. Pkh1 and 2 are redundant proteins involved in multiple essential cellular functions, including endocytosis and cell wall integrity. Based on similarities with the budding yeast, the Pkh of fungal infectious species was postulated as a novel target for antifungals. Here, we found that depletion of Pkh eventually induces oxidative stress and DNA double-strand breaks, leading to programmed cell death. This finding supports Pkh as an antifungal target since pharmacological inhibition of Pkh would lead to the death of yeast cells, the ultimate goal of antifungals. It was therefore of interest to further investigate the possibility to develop Pkh inhibitors with selectivity for Candida Pkh that would not inhibit the human ortholog. Here, we describe C. albicans Pkh2 biochemically, structurally and by using chemical probes in comparison to human PDK1. We found that a regulatory site on the C. albicans Pkh2 catalytic domain, the PIF-pocket, diverges from human PDK1. Indeed, we identified and characterized PS77, a new small allosteric inhibitor directed to the PIF-pocket, which has increased selectivity for C. albicans Pkh2. Together, our results describe novel features of the biology of Pkh and chemical biology approaches that support the validation of Pkh as a drug target for selective antifungals. | ||
| 653 | 0 | |a 2 [3 [4 CHLOROPHENYL] 1 [2 [4 CHLOROPHENYLTHIO]PHENYL] 3 OXOPROPYLTHIO]ACETIC ACID | |
| 653 | 0 | |a ANTIFUNGAL AGENT | |
| 653 | 0 | |a FUNGAL PROTEIN | |
| 653 | 0 | |a PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1 | |
| 653 | 0 | |a PKH1 PROTEIN | |
| 653 | 0 | |a PKH2 PROTEIN | |
| 653 | 0 | |a PROTEIN INHIBITOR | |
| 653 | 0 | |a PS 77 | |
| 653 | 0 | |a REACTIVE OXYGEN METABOLITE | |
| 653 | 0 | |a UNCLASSIFIED DRUG | |
| 653 | 0 | |a ALLOSTERISM | |
| 653 | 0 | |a APOPTOSIS | |
| 653 | 0 | |a CANDIDA ALBICANS | |
| 653 | 0 | |a CONTROLLED STUDY | |
| 653 | 0 | |a DOUBLE STRANDED DNA BREAK | |
| 653 | 0 | |a DRUG MECHANISM | |
| 653 | 0 | |a DRUG TARGETING | |
| 653 | 0 | |a ENDOCYTOSIS | |
| 653 | 0 | |a ENZYME PHOSPHORYLATION | |
| 653 | 0 | |a FUNGAL CELL WALL | |
| 653 | 0 | |a FUNGAL GENE | |
| 653 | 0 | |a FUNGAL STRAIN | |
| 653 | 0 | |a NONHUMAN | |
| 653 | 0 | |a OXIDATIVE STRESS | |
| 653 | 0 | |a PROTEIN DOMAIN | |
| 653 | 0 | |a YEAST CELL | |
| 700 | 1 | |a Pastor Flores, Daniel |9 72473 | |
| 700 | 1 | |a Schulze, Jörg O. |9 72474 | |
| 700 | 1 | |a Bahí, Anna |9 72475 | |
| 700 | 1 | |9 68244 |a Giacometti, Romina | |
| 700 | 1 | |a Ferrer Dalmau, Jofre |9 72476 | |
| 700 | 1 | |9 48345 |a Passeron, Susana | |
| 700 | 1 | |a Engel, Matthias |9 72477 | |
| 700 | 1 | |a Süß, Evelyn |9 72478 | |
| 700 | 1 | |a Casamayor, Antonio |9 72479 | |
| 700 | 1 | |a Biondi, Ricardo M. |9 69374 | |
| 773 | |t ACS Chemical Biology |g vol.8, no.10 (2013), p.2283-2292 | ||
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| 900 | |a ^tPIF-pocket as a target for C. albicans Pkh selective inhibitors | ||
| 900 | |a ^aPastor-Flores^bD. | ||
| 900 | |a ^aSchulze^bJ.O. | ||
| 900 | |a ^aBahí^bA. | ||
| 900 | |a ^aGiacometti^bR. | ||
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| 900 | |a ^aCasamayor^bA. | ||
| 900 | |a ^aBiondi^bR.M. | ||
| 900 | |a ^aPastor Flores^bD. | ||
| 900 | |a ^aSchulze^bJ. O. | ||
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| 900 | |a ^aGiacometti^bR. | ||
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| 900 | |a ^aPasseron^bS. | ||
| 900 | |a ^aEngel^bM. | ||
| 900 | |a ^aSüß^bE. | ||
| 900 | |a ^aCasamayor^bA. | ||
| 900 | |a ^aBiondi^bR. M. | ||
| 900 | |a ^aPastor-Flores^bD.^tResearch Group PhosphoSites, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany | ||
| 900 | |a ^aSchulze^bJ.O.^tResearch Group PhosphoSites, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany | ||
| 900 | |a ^aBahí^bA.^tDepartament de Bioquímica i Biologia Molecular, Facultat de Veterinària, Universitat Autònoma de Barcelona, Cerdanyola 08193, Barcelona, Spain | ||
| 900 | |a ^aGiacometti^bR.^tCátedra de Bioquímica, Facultad de Agronomía, Universidad de Buenos Aires, C1417DSE Buenos Aires, Argentina | ||
| 900 | |a ^aFerrer-Dalmau^bJ.^tDepartament de Bioquímica i Biologia Molecular, Facultat de Veterinària, Universitat Autònoma de Barcelona, Cerdanyola 08193, Barcelona, Spain | ||
| 900 | |a ^aPasseron^bS.^tCátedra de Bioquímica, Facultad de Agronomía, Universidad de Buenos Aires, C1417DSE Buenos Aires, Argentina | ||
| 900 | |a ^aEngel^bM.^tPharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany | ||
| 900 | |a ^aSüß^bE.^tResearch Group PhosphoSites, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany | ||
| 900 | |a ^aCasamayor^bA.^tDepartament de Bioquímica i Biologia Molecular, Facultat de Veterinària, Universitat Autònoma de Barcelona, Cerdanyola 08193, Barcelona, Spain | ||
| 900 | |a ^aBiondi^bR.M.^tResearch Group PhosphoSites, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany | ||
| 900 | |a ^aBahí^bA.^tInstitut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola 08193, Barcelona, Spainn | ||
| 900 | |a ^aFerrer-Dalmau^bJ.^tInstitut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola 08193, Barcelona, Spainn | ||
| 900 | |a ^aCasamayor^bA.^tInstitut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola 08193, Barcelona, Spain | ||
| 900 | |a ^tACS Chemical Biology^cACS Chem. Biol. | ||
| 900 | |a en | ||
| 900 | |a 2283 | ||
| 900 | |a ^i | ||
| 900 | |a Vol. 8, no. 10 | ||
| 900 | |a 2292 | ||
| 900 | |a 2 [3 [4 CHLOROPHENYL] 1 [2 [4 CHLOROPHENYLTHIO]PHENYL] 3 OXOPROPYLTHIO]ACETIC ACID | ||
| 900 | |a ANTIFUNGAL AGENT | ||
| 900 | |a FUNGAL PROTEIN | ||
| 900 | |a PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1 | ||
| 900 | |a PKH1 PROTEIN | ||
| 900 | |a PKH2 PROTEIN | ||
| 900 | |a PROTEIN INHIBITOR | ||
| 900 | |a PS 77 | ||
| 900 | |a REACTIVE OXYGEN METABOLITE | ||
| 900 | |a UNCLASSIFIED DRUG | ||
| 900 | |a ALLOSTERISM | ||
| 900 | |a APOPTOSIS | ||
| 900 | |a CANDIDA ALBICANS | ||
| 900 | |a CONTROLLED STUDY | ||
| 900 | |a DOUBLE STRANDED DNA BREAK | ||
| 900 | |a DRUG MECHANISM | ||
| 900 | |a DRUG TARGETING | ||
| 900 | |a ENDOCYTOSIS | ||
| 900 | |a ENZYME PHOSPHORYLATION | ||
| 900 | |a FUNGAL CELL WALL | ||
| 900 | |a FUNGAL GENE | ||
| 900 | |a FUNGAL STRAIN | ||
| 900 | |a NONHUMAN | ||
| 900 | |a OXIDATIVE STRESS | ||
| 900 | |a PROTEIN DOMAIN | ||
| 900 | |a YEAST CELL | ||
| 900 | |a The phosphoinositide-dependent protein kinase 1, PDK1, is a master kinase that phosphorylates the activation loop of up to 23 AGC kinases. S. cerevisiae has three PDK1 orthologues, Pkh1-3, which also phosphorylate AGC kinases [e.g., Ypk, Tpk, Pkc1, and Sch9]. Pkh1 and 2 are redundant proteins involved in multiple essential cellular functions, including endocytosis and cell wall integrity. Based on similarities with the budding yeast, the Pkh of fungal infectious species was postulated as a novel target for antifungals. Here, we found that depletion of Pkh eventually induces oxidative stress and DNA double-strand breaks, leading to programmed cell death. This finding supports Pkh as an antifungal target since pharmacological inhibition of Pkh would lead to the death of yeast cells, the ultimate goal of antifungals. It was therefore of interest to further investigate the possibility to develop Pkh inhibitors with selectivity for Candida Pkh that would not inhibit the human ortholog. Here, we describe C. albicans Pkh2 biochemically, structurally and by using chemical probes in comparison to human PDK1. We found that a regulatory site on the C. albicans Pkh2 catalytic domain, the PIF-pocket, diverges from human PDK1. Indeed, we identified and characterized PS77, a new small allosteric inhibitor directed to the PIF-pocket, which has increased selectivity for C. albicans Pkh2. Together, our results describe novel features of the biology of Pkh and chemical biology approaches that support the validation of Pkh as a drug target for selective antifungals. | ||
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