Unique Structure and Dynamics of the EphA5 Ligand Binding Domain Mediate Its Binding Specificity as Revealed by X-ray Crystallography, NMR and MD Simulations
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The 16 EphA and EphB receptors represent the largest family of receptor tyrosine kinases, and their interactions with 9 ephrin-A and ephrin-B ligands initiate bidirectional signals controlling many physiological and pathological processes. Most interactions occur between receptor and ephrins of the same class, and only EphA4 can bind all A and B ephrins. To understand the structural and dynamic principles that enable Eph receptors to utilize the same jellyroll β-sandwich fold to bind ephrins, the VAPB-MSP domain, peptides and small molecules, we have used crystallography, NMR and molecular dynamics (MD) simulations to determine the first structure and dynamics of the EphA5 ligand-binding domain (LBD), which only binds ephrin-A ligands. Unexpectedly, despite being unbound, the high affinity ephrin-binding pocket of EphA5 resembles that of other Eph receptors bound to ephrins, with a helical conformation over the J-K loop and an open pocket. The openness of the pocket is further supported by NMR hydrogen/deuterium exchange data and MD simulations. Additionally, the EphA5 LBD undergoes significant picosecond-nanosecond conformational exchanges over the loops, as revealed by NMR and MD simulations, but lacks global conformational exchanges on the microsecond-millisecond time scale. This is markedly different from the EphA4 LBD, which shares 74% sequence identity and 87% homology. Consequently, the unbound EphA5 LBD appears to comprise an ensemble of open conformations that have only small variations over the loops and appear ready to bind ephrin-A ligands. These findings show how two proteins with high sequence homology and structural similarity are still able to achieve distinctive binding specificities through different dynamics, which may represent a general mechanism whereby the same protein fold can serve for different functions. Our findings also suggest that a promising strategy to design agonists/antagonists with high affinity and selectivity might be to target specific dynamic states of the Eph receptor LBDs.
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Conformational dynamics and the distribution of the conformational ensemble are important in Eph-ephrin recognition.
“Conformational dynamics and the distribution of the conformational ensemble are important in Eph-Ephrin recognition.9,475,513–516”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [516]
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- Authors
- Huan, X., Shi, J., Lim, L., Mitra, S., Zhu, W., Qin, H., Pasquale, E. B., & Song, J.
- Affiliations
- National University of Singapore (SG)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Song, Jianxing
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-09-24
- Volume
- 8
- Issue
- 9
- Pages
- e74040
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3782497
- OpenAlex
- W1966357275
- Cited by
- 16
- References
- 70
- Citations by year
- 2025: 1 · 2021: 3 · 2020: 2 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 1
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Ministry of Education, India
- National Institutes of Health (Tier 2)
- Medical Research Council
- National Medical Research Council (R-154-000-382-213)
- National Cancer Institute (P01CA138390)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- 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
- Keywords
- EphA5, ligand-binding domain, ephrin-A, receptor tyrosine kinase, binding specificity, conformational dynamics, hydrogen-deuterium exchange, EphA4, ligand-receptor interactions, protein conformational ensembles
- MeSH terms
- Base Sequence, Binding Sites, Humans, Ligands, Protein Conformation, DNA Primers, Crystallography, X-Ray, Nuclear Magnetic Resonance, Biomolecular, Receptor, EphA5, Molecular Dynamics Simulation
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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