Literature DB >> 23509259

Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1.

Ethan G Geier1, Avner Schlessinger, Hao Fan, Jonathan E Gable, John J Irwin, Andrej Sali, Kathleen M Giacomini.   

Abstract

The Large-neutral Amino Acid Transporter 1 (LAT-1)--a sodium-independent exchanger of amino acids, thyroid hormones, and prescription drugs--is highly expressed in the blood-brain barrier and various types of cancer. LAT-1 plays an important role in cancer development as well as in mediating drug and nutrient delivery across the blood-brain barrier, making it a key drug target. Here, we identify four LAT-1 ligands, including one chemically novel substrate, by comparative modeling, virtual screening, and experimental validation. These results may rationalize the enhanced brain permeability of two drugs, including the anticancer agent acivicin. Finally, two of our hits inhibited proliferation of a cancer cell line by distinct mechanisms, providing useful chemical tools to characterize the role of LAT-1 in cancer metabolism.

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Year:  2013        PMID： 23509259      PMCID： PMC3619328          DOI： 10.1073/pnas.1218165110

Source DB:  PubMed          Journal:  Proc Natl Acad Sci U S A        ISSN： 0027-8424            Impact factor:   11.205


  55 in total

Review 1.  CATs and HATs: the SLC7 family of amino acid transporters.

Authors:  François Verrey; Ellen I Closs; Carsten A Wagner; Manuel Palacin; Hitoshi Endou; Yoshikatsu Kanai
Journal:  Pflugers Arch       Date:  2003-06-11       Impact factor: 3.657

2.  Comparative protein modelling by satisfaction of spatial restraints.

Authors:  A Sali; T L Blundell
Journal:  J Mol Biol       Date:  1993-12-05       Impact factor: 5.469

3.  A simple method for displaying the hydropathic character of a protein.

Authors:  J Kyte; R F Doolittle
Journal:  J Mol Biol       Date:  1982-05-05       Impact factor: 5.469

4.  Acivicin: a new glutamine antagonist in clinical trials.

Authors:  P J O'Dwyer; M T Alonso; B Leyland-Jones
Journal:  J Clin Oncol       Date:  1984-09       Impact factor: 44.544

5.  Simple allosteric model for membrane pumps.

Authors:  O Jardetzky
Journal:  Nature       Date:  1966-08-27       Impact factor: 49.962

6.  P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists.

Authors:  B J Smith; A C Doran; S McLean; F D Tingley; B T O'Neill; S M Kajiji
Journal:  J Pharmacol Exp Ther       Date:  2001-09       Impact factor: 4.030

7.  Phase II trial of acivicin versus etoposide-cisplatin in non-small cell lung cancer. An Eastern Cooperative Oncology Group study.

Authors:  P Bonomi; D Finkelstein; A Chang
Journal:  Am J Clin Oncol       Date:  1994-06       Impact factor: 2.339

8.  Comparative biodistribution of iodinated amino acids in rats: selection of the optimal analog for oncologic imaging outside the brain.

Authors:  Tony Lahoutte; John Mertens; Vicky Caveliers; Philippe R Franken; Hendrik Everaert; Axel Bossuyt
Journal:  J Nucl Med       Date:  2003-09       Impact factor: 10.057

9.  Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation.

Authors:  L M Roberts; D S Black; C Raman; K Woodford; M Zhou; J E Haggerty; A T Yan; S E Cwirla; K K Grindstaff
Journal:  Neuroscience       Date:  2008-06-13       Impact factor: 3.590

10.  The Universal Protein Resource (UniProt) in 2010.

Authors: 
Journal:  Nucleic Acids Res       Date:  2009-10-20       Impact factor: 16.971
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  75 in total

1.  LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs.

Authors:  Evan Augustyn; Karissa Finke; Arik A Zur; Logan Hansen; Nathan Heeren; Huan-Chieh Chien; Lawrence Lin; Kathleen M Giacomini; Claire Colas; Avner Schlessinger; Allen A Thomas
Journal:  Bioorg Med Chem Lett       Date:  2016-04-11       Impact factor: 2.823

2.  Structural insights into thyroid hormone transport mechanisms of the L-type amino acid transporter 2.

Authors:  Katrin M Hinz; Katja Meyer; Anita Kinne; Ralf Schülein; Josef Köhrle; Gerd Krause
Journal:  Mol Endocrinol       Date:  2015-05-06

3.  Structure-Based Identification of Inhibitors for the SLC13 Family of Na(+)/Dicarboxylate Cotransporters.

Authors:  Claire Colas; Ana M Pajor; Avner Schlessinger
Journal:  Biochemistry       Date:  2015-07-30       Impact factor: 3.162

Review 4.  Hypoxia and cellular metabolism in tumour pathophysiology.

Authors:  Scott K Parks; Yann Cormerais; Jacques Pouysségur
Journal:  J Physiol       Date:  2017-02-19       Impact factor: 5.182

5.  Few Amino Acid Exchanges Expand the Substrate Spectrum of Monocarboxylate Transporter 10.

Authors:  Jörg Johannes; Doreen Braun; Anita Kinne; Daniel Rathmann; Josef Köhrle; Ulrich Schweizer
Journal:  Mol Endocrinol       Date:  2016-05-31

6.  Insights into the molecular basis for substrate binding and specificity of the wild-type L-arginine/agmatine antiporter AdiC.

Authors:  Hüseyin Ilgü; Jean-Marc Jeckelmann; Vytautas Gapsys; Zöhre Ucurum; Bert L de Groot; Dimitrios Fotiadis
Journal:  Proc Natl Acad Sci U S A       Date:  2016-08-31       Impact factor: 11.205

7.  Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies.

Authors:  Sook Wah Yee; Dina Buitrago; Adrian Stecula; Huy X Ngo; Huan-Chieh Chien; Ling Zou; Megan L Koleske; Kathleen M Giacomini
Journal:  FASEB J       Date:  2020-10-30       Impact factor: 5.191

8.  Prazosin induced lysosomal tubulation interferes with cytokinesis and the endocytic sorting of the tumour antigen CD98hc.

Authors:  Robert Fuchs; Anika Stracke; Viktoria Holzmann; Gerfried Luschin-Ebengreuth; Nathalie Meier-Allard; Nadine Ebner; Teresa Maria Lassacher; Markus Absenger-Novak; Eleonore Fröhlich; Matthias Schittmayer; Sara Cano Crespo; Manuel Palacin; Beate Rinner; Ruth Birner-Gruenberger
Journal:  Biochim Biophys Acta Mol Cell Res       Date:  2018-06-15       Impact factor: 4.739

9.  LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates.

Authors:  Arik A Zur; Huan-Chieh Chien; Evan Augustyn; Andrew Flint; Nathan Heeren; Karissa Finke; Christopher Hernandez; Logan Hansen; Sydney Miller; Lawrence Lin; Kathleen M Giacomini; Claire Colas; Avner Schlessinger; Allen A Thomas
Journal:  Bioorg Med Chem Lett       Date:  2016-09-03       Impact factor: 2.823

10.  Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.

Authors:  Peter Man-Un Ung; Wenxin Song; Lili Cheng; Xinbin Zhao; Hailin Hu; Ligong Chen; Avner Schlessinger
Journal:  ACS Chem Biol       Date:  2016-05-11       Impact factor: 5.100
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