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Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase.
Gritzalis, Dimitrios; Park, Jaeok; Chiu, Wei; Cho, Hyungjun; Lin, Yih-Shyan; De Schutter, Joris W; Lacbay, Cyrus M; Zielinski, Michal; Berghuis, Albert M; Tsantrizos, Youla S.
Afiliación
  • Gritzalis D; Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
  • Park J; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
  • Chiu W; Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
  • Cho H; Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
  • Lin YS; Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
  • De Schutter JW; Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
  • Lacbay CM; Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
  • Zielinski M; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
  • Berghuis AM; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Department of Microbiology and Immunology, McGill University, 3775 Rue University, Montreal, QC H3A 2B4, Canada; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3
  • Tsantrizos YS; Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3649 Promena
Bioorg Med Chem Lett ; 25(5): 1117-23, 2015 Mar 01.
Article en En | MEDLINE | ID: mdl-25630225
ABSTRACT
In order to explore the interactions of bisphosphonate ligands with the active site and an allosteric pocket of the human farnesyl pyrophosphate synthase (hFPPS), substituted indole and azabenzimidazole bisphosphonates were designed as chameleon ligands. NMR and crystallographic studies revealed that these compounds can occupy both sub-pockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg(2+) ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feed-back regulatory role for this enzyme.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Difosfonatos / Geraniltranstransferasa Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Canadá
Texto completo
Imprimir
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Difosfonatos / Geraniltranstransferasa Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Canadá