Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
J Mol Biol ; 436(3): 168411, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38135181

RESUMEN

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor belonging to the bHLH/PAS protein family and responding to hundreds of natural and chemical substances. It is primarily involved in the defense against chemical insults and bacterial infections or in the adaptive immune response, but also in the development of pathological conditions ranging from inflammatory to neoplastic disorders. Despite its prominent roles in many (patho)physiological processes, the lack of high-resolution structural data has precluded for thirty years an in-depth understanding of the structural mechanisms underlying ligand-binding specificity, promiscuity and activation of AHR. We recently reported a cryogenic electron microscopy (cryo-EM) structure of human AHR bound to the natural ligand indirubin, the chaperone Hsp90 and the co-chaperone XAP2 that provided the first experimental visualization of its ligand-binding PAS-B domain. Here, we report a 2.75 Å resolution structure of the AHR complex bound to the environmental pollutant benzo[a]pyrene (B[a]P). The structure substantiates the existence of a bipartite PAS-B ligand-binding pocket with a geometrically constrained primary binding site controlling ligand binding specificity and affinity, and a secondary binding site contributing to the binding promiscuity of AHR. We also report a docking study of B[a]P congeners that validates the B[a]P-bound PAS-B structure as a suitable model for accurate computational ligand binding assessment. Finally, comparison of our agonist-bound complex with the recently reported structures of mouse and fruit fly AHR PAS-B in different activation states suggests a ligand-induced loop conformational change potentially involved in the regulation of AHR function.


Asunto(s)
Benzo(a)pireno , Contaminantes Ambientales , Receptores de Hidrocarburo de Aril , Humanos , Benzo(a)pireno/química , Sitios de Unión , Ligandos , Dominios Proteicos , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/química , Contaminantes Ambientales/química
2.
Nat Commun ; 13(1): 7010, 2022 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-36385050

RESUMEN

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a broad spectrum of (patho)physiological processes in response to numerous substances including pollutants, natural products and metabolites. However, the scarcity of structural data precludes understanding of how AHR is activated by such diverse compounds. Our 2.85 Å structure of the human indirubin-bound AHR complex with the chaperone Hsp90 and the co-chaperone XAP2, reported herein, reveals a closed conformation Hsp90 dimer with AHR threaded through its lumen and XAP2 serving as a brace. Importantly, we disclose the long-awaited structure of the AHR PAS-B domain revealing a unique organisation of the ligand-binding pocket and the structural determinants of ligand-binding specificity and promiscuity of the receptor. By providing structural details of the molecular initiating event leading to AHR activation, our study rationalises almost forty years of biochemical data and provides a framework for future mechanistic studies and structure-guided drug design.


Asunto(s)
Proteínas HSP90 de Choque Térmico , Péptidos y Proteínas de Señalización Intracelular , Receptores de Hidrocarburo de Aril , Humanos , Microscopía por Crioelectrón , Citosol/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Receptores de Hidrocarburo de Aril/metabolismo
3.
Mol Plant ; 14(5): 829-837, 2021 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-33684542

RESUMEN

Pioneer transcription factors (TFs) are a special category of TFs with the capacity to bind to closed chromatin regions in which DNA is wrapped around histones and may be highly methylated. Subsequently, pioneer TFs are able to modify the chromatin state to initiate gene expression. In plants, LEAFY (LFY) is a master floral regulator and has been suggested to act as a pioneer TF in Arabidopsis. Here, we demonstrate that LFY is able to bind both methylated and non-methylated DNA using a combination of in vitro genome-wide binding experiments and structural modeling. Comparisons between regions bound by LFY in vivo and chromatin accessibility data suggest that a subset of LFY bound regions is occupied by nucleosomes. We confirm that LFY is able to bind nucleosomal DNA in vitro using reconstituted nucleosomes. Finally, we show that constitutive LFY expression in seedling tissues is sufficient to induce chromatin accessibility in the LFY direct target genes APETALA1 and AGAMOUS. Taken together, our study suggests that LFY possesses key pioneer TF features that contribute to launching the floral gene expression program.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/citología , Flores/citología , Plantones/genética , Factores de Transcripción/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Cromatina/metabolismo , Flores/genética , Regulación de la Expresión Génica de las Plantas , Histonas/metabolismo , Nucleosomas/metabolismo , Plantas Modificadas Genéticamente , Factores de Transcripción/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...