Protein dynamics at Eph receptor-ligand interfaces as revealed by crystallography, NMR and MD simulations
Open accessAbstract
Background: The role of dynamics in protein functions including signal transduction is just starting to be deciphered. Eph receptors with 16 members divided into A- and B- subclasses are respectively activated by 9 A- and B-ephrin ligands. EphA4 is the only receptor capable of binding to all 9 ephrins and small molecules with overlapped interfaces. Results: We first determined the structures of the EphA4 ligand binding domain (LBD) in two crystals of P1 space group. Noticeably, 8 EphA4 molecules were found in one asymmetric unit and consequently from two crystals we obtained 16 structures, which show significant conformational variations over the functionally critical A-C, D-E, G-H and J-K loops. The 16 new structures, together with previous 9 ones, can be categorized into two groups: closed and open forms which resemble the uncomplexed and complexed structures of the EphA4 LBD respectively. To assess whether the conformational diversity over the loops primarily results from the intrinsic dynamics, we initiated 30-ns molecular dynamics (MD) simulations for both closed and open forms. The results indicate that the loops do have much higher intrinsic dynamics, which is further unravelled by NMR H/D exchange experiments. During simulations, the open form has the RMS deviations slightly larger than those of the closed one, suggesting the open form may be less stable in the absence of external contacts. Furthermore, no obvious exchange between two forms is observed within 30 ns, implying that they are dynamically separated. Conclusions: Our study provides the first experimental and computational result revealing that the intrinsic dynamics are most likely underlying the conformational diversity observed for the EphA4 LBD loops mediating the binding affinity and specificity. Interestingly, the open conformation of the EphA4 LBD is slightly unstable in the absence of it natural ligand ephrins, implying that the conformational transition from the closed to open has to be driven by the high-affinity interaction with ephrins because the weak interaction with small molecule was found to be insufficient to trigger the transition. Our results therefore highlight the key role of protein dynamics in Eph-ephrin signalling and would benefit future design of agonists/antagonists targeting Eph receptors.
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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 [9]
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- Authors
- Qin, H., Lim, L., & Song, J.
- Affiliations
- National University of Singapore (SG)
- Corresponding author
- Song, Jianxing
- Venue
- BMC Biophysics
- Published
- 2012-01-25
- Volume
- 5
- Issue
- 1
- Pages
- 2-2
- ISSN
- 2046-1682 (ISSN-L)
- PMC
- PMC3274464
- OpenAlex
- W1987441978
- Cited by
- 23
- References
- 63
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 1 · 2014: 5 · 2013: 4 · 2012: 3
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- BMC Biophysics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center
- Medical Research Council
- National Medical Research Council (R-154-000-382-213)
- 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
- EphA4, ephrins, ligand-binding domain, conformational heterogeneity, loop flexibility, hydrogen-deuterium exchange
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