Cited by 14Protein Structure and DynamicsReceptor Mechanisms and SignalingEnzyme Structure and Function

Accelerated Molecular Dynamics and AlphaFold Uncover a Missing Conformational State of Transporter Protein OxlT

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Ohnuki, Jun, Jaunet-Lahary, Titouan, Yamashita, Atsuko, Okazaki, Kei-ichi·2024·The Journal of Physical Chemistry Letters

Published version of a preprint

Abstract

ABSTRACT Transporter proteins change their conformation to carry their substrate across the cell membrane. The conformational dynamics are vital to understanding the transport function. We have studied the oxalate transporter (OxlT), an oxalate:formate antiporter from Oxalobacter formigenes , significant in avoiding kidney stone formation. The atomic structure of OxlT has been recently solved in the outward-open and occluded states. However, the inward-open conformation is still missing, hindering a complete understanding of the transporter. Here, we performed an accelerated molecular dynamics simulation to sample the extensive conformational space of OxlT and successfully obtained the inward-open conformation where cytoplasmic substrate formate binding was preferred over oxalate binding. We also identified critical interactions for the inward- open conformation. The results were complemented by the highly accurate structure prediction by AlphaFold2. Although AlphaFold2 solely predicted OxlT in the outward-open conformation, mutation of the identified critical residues made it partly predict the inward-open conformation, identifying possible state-shifting mutations. TOC GRAPHICS

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Authors
Ohnuki, J., Jaunet-Lahary, T., Yamashita, A., & Okazaki, K.-I.
Affiliations
  • National Institutes of Natural Sciences (JP)
  • Research Center for Computational Science, Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki 444-8585, Japan
  • Okayama University (JP)
Corresponding author
Okazaki, Kei-ichi
Venue
The Journal of Physical Chemistry Letters
Published
2024-01-12
Volume
15
Issue
3
Pages
725-732
ISSN
1948-7185 (ISSN-L)
OpenAlex
W4390830169
Cited by
14
References
41
Citations by year
2026: 5 · 2025: 5 · 2024: 4
FWCI
1.91
Type
journal article
Language
en
Open access
Locations
  • The Journal of Physical Chemistry Letters (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • Japan Society for the Promotion of Science (JP23K14160, JP22H02595)
  • Nagase Science Technology Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
Oxalobacter formigenes, transporter conformational states, inward-open conformation, outward-open conformation, occluded state, accelerated molecular dynamics, AlphaFold2, oxalate binding, kidney stone prevention
MeSH terms
Formates, Oxalates, Protein Conformation, Antiporters, Membrane Transport Proteins, Molecular Dynamics Simulation

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