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The full spectrum o...
The full spectrum of SLC22 OCT1 mutations illuminates the bridge between drug transporter biophysics and pharmacogenomics
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- Yee, Sook Wah (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- Macdonald, Christian B. (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- 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
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- Koleske, Megan L. (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- Yang, Jia (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- Buitrago Silva, Dina (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- Rockefeller Grimes, Patrick (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- Trinidad, Donovan D. (författare)
- Department of Medicine, Division of Infectious Disease, University of California, San Francisco, San Francisco, CA 94143, USA
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- More, Swati S. (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- Kachuri, Linda (författare)
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA
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- 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
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- Delemotte, Lucie (författare)
- KTH,Biofysik,Science for Life Laboratory, SciLifeLab
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- Giacomini, Kathleen M. (författare)
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
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- 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.
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Ingår i: Molecular Cell. - : Cell Press. - 1097-2765 .- 1097-4164. ; 84:10, s. 10-1932
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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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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- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Yee, Sook Wah
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Macdonald, Chris ...
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Mitrovic, Darko
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Zhou, Xujia
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Koleske, Megan L ...
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Yang, Jia
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visa fler...
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Buitrago Silva, ...
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Rockefeller Grim ...
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Trinidad, Donova ...
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More, Swati S.
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Kachuri, Linda
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Witte, John S.
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Delemotte, Lucie
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Giacomini, Kathl ...
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Coyote-Maestas, ...
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- Om ämnet
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- NATURVETENSKAP
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NATURVETENSKAP
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och Biologi
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och Biofysik
- Artiklar i publikationen
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Molecular Cell
- Av lärosätet
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Kungliga Tekniska Högskolan