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The full spectrum of SLC22 OCT1 mutations illuminates the bridge between drug transporter biophysics and pharmacogenomics

Yee, Sook Wah (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Macdonald, Christian B. (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Mitrovic, Darko (författare)
KTH,Biofysik,Science for Life Laboratory, SciLifeLab
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Zhou, Xujia (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Koleske, Megan L. (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Yang, Jia (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Buitrago Silva, Dina (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Rockefeller Grimes, Patrick (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Trinidad, Donovan D. (författare)
Department of Medicine, Division of Infectious Disease, University of California, San Francisco, San Francisco, CA 94143, USA
More, Swati S. (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Kachuri, Linda (författare)
Department of Epidemiology and Population Health, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA
Witte, John S. (författare)
Department of Epidemiology and Population Health, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA
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, San Francisco, CA 94143, USA
Coyote-Maestas, Willow (författare)
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94148, USA
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 (creator_code:org_t)
Cell Press, 2024
2024
Engelska.
Ingår i: Molecular Cell. - : Cell Press. - 1097-2765 .- 1097-4164. ; 84:10, s. 10-1932
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • Mutations in transporters can impact an individual's response to drugs and cause many diseases. Few variants in transporters have been evaluated for their functional impact. Here, we combine saturation mutagenesis and multi-phenotypic screening to dissect the impact of 11,213 missense single-amino-acid deletions, and synonymous variants across the 554 residues of OCT1, a key liver xenobiotic transporter. By quantifying in parallel expression and substrate uptake, we find that most variants exert their primary effect on protein abundance, a phenotype not commonly measured alongside function. Using our mutagenesis results combined with structure prediction and molecular dynamic simulations, we develop accurate structure-function models of the entire transport cycle, providing biophysical characterization of all known and possible human OCT1 polymorphisms. This work provides a complete functional map of OCT1 variants along with a framework for integrating functional genomics, biophysical modeling, and human genetics to predict variant effects on disease and drug efficacy.

Ämnesord

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

Nyckelord

deep mutational scanning
drug transporter
membrane protein folding
OCT1
pharmacogenomics
precision medicine
SLC22
structure prediction
structure-function

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