Show simple item record

dc.contributor.author
Yan, Renhong
dc.contributor.author
Li, Yaning
dc.contributor.author
Müller, Jennifer
dc.contributor.author
Zhang, Yuanyuan
dc.contributor.author
Singer, Simon
dc.contributor.author
Xia, Lu
dc.contributor.author
Zhong, Xinyue
dc.contributor.author
Gertsch, Jürg
dc.contributor.author
Altmann, Karl-Heinz
dc.contributor.author
Zhou, Qiang
dc.date.accessioned
2021-04-12T13:36:35Z
dc.date.available
2021-04-03T02:56:40Z
dc.date.available
2021-04-12T13:36:35Z
dc.date.issued
2021-03-23
dc.identifier.issn
2056-5968
dc.identifier.other
10.1038/s41421-021-00247-4
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/477383
dc.identifier.doi
10.3929/ethz-b-000477383
dc.description.abstract
LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in many types of tumors and mediates the transfer of drugs and hormones across the blood-brain barrier. Thus, LAT1 is considered as a drug target for cancer treatment and may be exploited for drug delivery into the brain. Here, we synthesized three potent inhibitors of human LAT1, which inhibit transport of leucine with IC values between 100 and 250 nM, and solved the cryo-EM structures of the corresponding LAT1-4F2hc complexes with these inhibitors bound at resolution of up to 2.7 or 2.8 Å. The protein assumes an outward-facing occluded conformation, with the inhibitors bound in the classical substrate binding pocket, but with their tails wedged between the substrate binding site and TM10 of LAT1. We also solved the complex structure of LAT1-4F2hc with 3,5-diiodo-l-tyrosine (Diiodo-Tyr) at 3.4 Å overall resolution, which revealed a different inhibition mechanism and might represent an intermediate conformation between the outward-facing occluded state mentioned above and the outward-open state. To our knowledge, this is the first time that the outward-facing conformation is revealed for the HAT family. Our results unveil more important insights into the working mechanisms of HATs and provide a structural basis for future drug design. 50
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Springer
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
Cryoelectron microscopy
en_US
dc.subject
Mechanisms of disease
en_US
dc.title
Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
Cell Discovery
ethz.journal.volume
7
en_US
ethz.journal.issue
1
en_US
ethz.journal.abbreviated
Cell Discov
ethz.pages.start
16
en_US
ethz.size
8 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03647 - Altmann, Karl-Heinz / Altmann, Karl-Heinz
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03647 - Altmann, Karl-Heinz / Altmann, Karl-Heinz
ethz.date.deposited
2021-04-03T02:56:50Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2021-04-12T13:36:57Z
ethz.rosetta.lastUpdated
2022-03-29T06:29:58Z
ethz.rosetta.versionExported
true
ethz.COinS
ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.atitle=Mechanism%20of%20substrate%20transport%20and%20inhibition%20of%20the%20human%20LAT1-4F2hc%20amino%20acid%20transporter&rft.jtitle=Cell%20Discovery&rft.date=2021-03-23&rft.volume=7&rft.issue=1&rft.spage=16&rft.issn=2056-5968&rft.au=Yan,%20Renhong&Li,%20Yaning&M%C3%BCller,%20Jennifer&Zhang,%20Yuanyuan&Singer,%20Simon&rft.genre=article&rft_id=info:doi/10.1038/s41421-021-00247-4&
 Search print copy at ETH Library

Files in this item

Thumbnail

Publication type

Show simple item record