Your browser doesn't support javascript.
loading
The full spectrum of OCT1 (SLC22A1) mutations bridges transporter biophysics to drug pharmacogenomics.
Yee, Sook Wah; Macdonald, Christian; Mitrovic, Darko; Zhou, Xujia; Koleske, Megan L; Yang, Jia; Silva, Dina Buitrago; Grimes, Patrick Rockefeller; Trinidad, Donovan; More, Swati S; Kachuri, Linda; Witte, John S; Delemotte, Lucie; Giacomini, Kathleen M; Coyote-Maestas, Willow.
Afiliação
  • Yee SW; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Macdonald C; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Mitrovic D; Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, 12121 Solna, Sweden.
  • Zhou X; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Koleske ML; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Yang J; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Silva DB; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Grimes PR; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Trinidad D; Department of Medicine, Division of Infectious Disease, University of California, San Francisco, United States.
  • More SS; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States.
  • Kachuri L; Current address: Center for Drug Design (CDD), College of Pharmacy, University of Minnesota, Minnesota, United States.
  • Witte JS; Epidemiology and Population Health, Stanford University, California, United States.
  • Delemotte L; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, United States.
  • Giacomini KM; Epidemiology and Population Health, Stanford University, California, United States.
  • Coyote-Maestas W; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, United States.
bioRxiv ; 2023 Jun 07.
Article em En | MEDLINE | ID: mdl-37333090
ABSTRACT
Membrane transporters play a fundamental role in the tissue distribution of endogenous compounds and xenobiotics and are major determinants of efficacy and side effects profiles. Polymorphisms within these drug transporters result in inter-individual variation in drug response, with some patients not responding to the recommended dosage of drug whereas others experience catastrophic side effects. For example, variants within the major hepatic Human organic cation transporter OCT1 (SLC22A1) can change endogenous organic cations and many prescription drug levels. To understand how variants mechanistically impact drug uptake, we systematically study how all known and possible single missense and single amino acid deletion variants impact expression and substrate uptake of OCT1. We find that human variants primarily disrupt function via folding rather than substrate uptake. Our study revealed that the major determinants of folding reside in the first 300 amino acids, including the first 6 transmembrane domains and the extracellular domain (ECD) with a stabilizing and highly conserved stabilizing helical motif making key interactions between the ECD and transmembrane domains. Using the functional data combined with computational approaches, we determine and validate a structure-function model of OCT1s conformational ensemble without experimental structures. Using this model and molecular dynamic simulations of key mutants, we determine biophysical mechanisms for how specific human variants alter transport phenotypes. We identify differences in frequencies of reduced function alleles across populations with East Asians vs European populations having the lowest and highest frequency of reduced function variants, respectively. Mining human population databases reveals that reduced function alleles of OCT1 identified in this study associate significantly with high LDL cholesterol levels. Our general approach broadly applied could transform the landscape of precision medicine by producing a mechanistic basis for understanding the effects of human mutations on disease and drug response.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos