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Structural basis of the acyl-transfer mechanism of human GPAT1.
Johnson, Zachary Lee; Ammirati, Mark; Wasilko, David Jonathan; Chang, Jeanne S; Noell, Stephen; Foley, Timothy L; Yoon, Hyejin; Smith, Kathleen; Asano, Shoh; Hales, Katherine; Wan, Min; Yang, Qingyi; Piotrowski, Mary A; Farley, Kathleen A; Gilbert, Tamara; Aschenbrenner, Lisa M; Fennell, Kimberly F; Dutra, Jason K; Xu, Mary; Guo, Chunyang; Varghese, Alison E; Bellenger, Justin; Quinn, Alandra; Am Ende, Christopher W; West, Graham M; Griffor, Matthew C; Bennett, Donald; Calabrese, Matthew; Steppan, Claire M; Han, Seungil; Wu, Huixian.
Afiliación
  • Johnson ZL; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Ammirati M; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Wasilko DJ; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Chang JS; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Noell S; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Foley TL; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Yoon H; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • Smith K; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • Asano S; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • Hales K; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • Wan M; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • Yang Q; Internal Medicine, Medicine Design, Pfizer Inc., Cambridge, MA, USA.
  • Piotrowski MA; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Farley KA; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Gilbert T; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • Aschenbrenner LM; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Fennell KF; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Dutra JK; Internal Medicine, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Xu M; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Guo C; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Varghese AE; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Bellenger J; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Quinn A; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Am Ende CW; Internal Medicine, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • West GM; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Griffor MC; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Bennett D; Biostatistics, Early Clinical Development, Pfizer Inc., Cambridge, MA, USA.
  • Calabrese M; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Steppan CM; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Han S; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA.
  • Wu H; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA. huixian.wu@pfizer.com.
Nat Struct Mol Biol ; 30(1): 22-30, 2023 01.
Article en En | MEDLINE | ID: mdl-36522428
Glycerol-3-phosphate acyltransferase (GPAT)1 is a mitochondrial outer membrane protein that catalyzes the first step of de novo glycerolipid biosynthesis. Hepatic expression of GPAT1 is linked to liver fat accumulation and the severity of nonalcoholic fatty liver diseases. Here we present the cryo-EM structures of human GPAT1 in substrate analog-bound and product-bound states. The structures reveal an N-terminal acyltransferase domain that harbors important catalytic motifs and a tightly associated C-terminal domain that is critical for proper protein folding. Unexpectedly, GPAT1 has no transmembrane regions as previously proposed but instead associates with the membrane via an amphipathic surface patch and an N-terminal loop-helix region that contains a mitochondrial-targeting signal. Combined structural, computational and functional studies uncover a hydrophobic pathway within GPAT1 for lipid trafficking. The results presented herein lay a framework for rational inhibitor development for GPAT1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Membranas Mitocondriales / Hígado Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Membranas Mitocondriales / Hígado Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos