The full spectrum of OCT1 (SLC22A1) mutations bridges transporter biophysics to drug pharmacogenomics

↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Sökning: WFRF:(Yee Sook Wah) > The full spectrum o...

The full spectrum of OCT1 (SLC22A1) mutations bridges transporter biophysics to drug pharmacogenomics

Yee, Sook Wah (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Macdonald, Christian (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Mitrovic, Darko (författare): KTH,Biofysik,Science for Life Laboratory, SciLifeLab

visa fler...

Zhou, Xujia (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Koleske, Megan L. (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Yiang, Jia (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Buitrago Silva, Dina (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Rockefeller Grimes, Patrick (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Trinidad, Donovan (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

More, Swati (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Kachuri, Linda (författare): Epidemiology and Population Health, Stanford University, California, United States

Witte, John (författare): Epidemiology and Population Health, Stanford University, California, United States

Delemotte, Lucie (författare): KTH,Biofysik,Science for Life Laboratory, SciLifeLab

Giacomini, Kathleen M. (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

Coyote-Maestas, Willow (författare): Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

visa färre...

(creator_code:org_t)

Engelska.

Relaterad länk:: https://www.biorxiv....; visa fler...; https://urn.kb.se/re...; visa färre...

Annan publikation (övrigt vetenskapligt/konstnärligt)

Abstract Ämnesord

Stäng

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.

Ämnesord

NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)

Nyckelord

Biologisk fysik
Biological Physics

Publikations- och innehållstyp

vet (ämneskategori)
ovr (ämneskategori)

Till lärosätets databas

Hitta mer i SwePub

Av författaren/redakt...: Yee, Sook Wah; Macdonald, Chris ...; Mitrovic, Darko; Zhou, Xujia; Koleske, Megan L ...; Yiang, Jia; visa fler...; Buitrago Silva, ...; Rockefeller Grim ...; Trinidad, Donova ...; More, Swati; Kachuri, Linda; Witte, John; Delemotte, Lucie; Giacomini, Kathl ...; Coyote-Maestas, ...; visa färre...

Om ämnet

NATURVETENSKAP: NATURVETENSKAP; och Biologi; och Biofysik

Av lärosätet: Kungliga Tekniska Högskolan

Sök utanför SwePub

Sök vidare i:: Google; Google Book Search; Google Scholar

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se