Artículo
Productive induced metastability in allosteric modulation of kinase function
Montes de Oca, Joan Manuel
; Rodriguez Fris, Jorge Ariel
; Appignanesi, Gustavo Adrian
; Fernandez, Ariel
Fecha de publicación:
07/2014
Editorial:
Wiley
Revista:
Febs Journal
ISSN:
1742-464X
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Allosteric modulators of kinase function are of considerable pharmacological interest as blockers or agonists of key cell-signaling pathways. They are gaining attention due to their purported higher selectivity and efficacy relative to ATP-competitive ligands. Upon binding to the target protein, allosteric inhibitors promote a conformational change that purposely facilitates or hampers ATP binding. However, allosteric binding remains a matter of contention because the binding site does not fit with a natural ligand (i.e. ATP or phosphorylation substrate) of the protein. In this study, we show that allosteric binding occurs by means of a local structural motif that promotes association with the ligand. We specifically show that allosteric modulators promote a local metastable state that is stabilized upon association. The induced conformational change generates a local enrichment of the protein in the so-called dehydrons, which are solvent-exposed backbone hydrogen bonds. These structural deficiencies that are inherently sticky are not present in the apo form and constitute a local metastable state that promotes association with the ligand. This productive induced metastability (PIM) is likely to translate into a general molecular design concept.
Palabras clave:
Pharmaceuticals
,
Dehydron
,
Allostery
,
Kinase Inhibitor
Archivos asociados
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Identificadores
Colecciones
Articulos(CCT - BAHIA BLANCA)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - BAHIA BLANCA
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - BAHIA BLANCA
Articulos(IAM)
Articulos de INST.ARG.DE MATEMATICAS "ALBERTO CALDERON"
Articulos de INST.ARG.DE MATEMATICAS "ALBERTO CALDERON"
Articulos(INQUISUR)
Articulos de INST.DE QUIMICA DEL SUR
Articulos de INST.DE QUIMICA DEL SUR
Articulos(INTEQUI)
Articulos de INST. DE INVEST. EN TECNOLOGIA QUIMICA
Articulos de INST. DE INVEST. EN TECNOLOGIA QUIMICA
Citación
Montes de Oca, Joan Manuel; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; Fernandez, Ariel; Productive induced metastability in allosteric modulation of kinase function; Wiley; Febs Journal; 281; 13; 7-2014; 3079-3091
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