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Accelerated Molecular Dynamics and AlphaFold Uncover a Missing Conformational State of Transporter Protein OxlT
Open accessPreprint — published as 10.1021/acs.jpclett.3c03052 · Paper page
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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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Sampling alternative conformational states of transporters and receptors with AlphaFold2
del Alamo, D., Sala, D., Mchaourab, H. S., & Meiler, J. (2022) · eLife · doi:10.7554/elife.75751 · Cited by 511
Impact of protein conformational diversity on AlphaFold predictions
Saldaño, T., Escobedo, N., Marchetti, J., Zea, D. J., Mac Donagh, J., Velez Rueda, A. J., Gonik, E., Melani, A. G., Novomisky Nechcoff, J., Salas, M. N., et al. (2021) · doi:10.1101/2021.10.27.466189 · Cited by 196 · cited 1×
“The prediction is usually biased to one conformation among possible conformations taken during the functional cycle, 33,34 which has been recently addressed by MSA subsampling, 15 masking, 16 or clustering 17 and template-based prediction.”
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Research works printed but not linked: 35
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Metadata
- Authors
- Ohnuki, J., Jaunet-Lahary, T., Yamashita, A., & Okazaki, K.-I.
- Affiliations
- National Institutes of Natural Sciences (JP)
- Okayama University (JP)
- Corresponding author
- Okazaki, Kei-ichi
- Venue
- The Journal of Physical Chemistry Letters
- Publisher
- openRxiv
- Published
- 2023-10-27
- Volume
- 15
- Issue
- 3
- Pages
- 725-732
- ISSN
- 1948-7185 (ISSN-L)
- OpenAlex
- W4390830169
- Cited by
- 14
- References
- 3
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- green
- dx.doi.org
- Locations
- The Journal of Physical Chemistry Letters (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Nagase Science Technology Foundation
- Japan Society for the Promotion of Science (JP22H02595, 23K23858, 23K14160)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › 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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- Ohnuki, J., Jaunet-Lahary, T., Yamashita, A., & Okazaki, K.-I. (2023). Accelerated Molecular Dynamics and AlphaFold Uncover a Missing Conformational State of Transporter Protein OxlT. The Journal of Physical Chemistry Letters. https://doi.org/10.1101/2023.10.26.564285
