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1.
Nat Chem Biol ; 8(11): 920-5, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23023261

RESUMEN

Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents.


Asunto(s)
Sitio Alostérico , Proteínas no Estructurales Virales/metabolismo , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Sitio Alostérico/genética , Antivirales/química , Antivirales/farmacología , Relación Dosis-Respuesta a Droga , Ligandos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Proteínas no Estructurales Virales/efectos de los fármacos , Proteínas no Estructurales Virales/genética
2.
ChemMedChem ; 9(4): 823-32, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24616449

RESUMEN

Soluble adenylate cyclases catalyse the synthesis of the second messenger cAMP through the cyclisation of ATP and are the only known enzymes to be directly activated by bicarbonate. Here, we report the first crystal structure of the human enzyme that reveals a pseudosymmetrical arrangement of two catalytic domains to produce a single competent active site and a novel discrete bicarbonate binding pocket. Crystal structures of the apo protein, the protein in complex with α,ß-methylene adenosine 5'-triphosphate (AMPCPP) and calcium, with the allosteric activator bicarbonate, and also with a number of inhibitors identified using fragment screening, all show a flexible active site that undergoes significant conformational changes on binding of ligands. The resulting nanomolar-potent inhibitors that were developed bind at both the substrate binding pocket and the allosteric site, and can be used as chemical probes to further elucidate the function of this protein.


Asunto(s)
Inhibidores de Adenilato Ciclasa , Bicarbonatos/farmacología , Inhibidores Enzimáticos/farmacología , Adenilil Ciclasas/química , Adenilil Ciclasas/metabolismo , Bicarbonatos/síntesis química , Bicarbonatos/química , Dominio Catalítico/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Relación Estructura-Actividad
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