Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels.
Journal
Communications chemistry
ISSN: 2399-3669
Titre abrégé: Commun Chem
Pays: England
ID NLM: 101725670
Informations de publication
Date de publication:
01 Jun 2024
01 Jun 2024
Historique:
received:
16
04
2024
accepted:
06
05
2024
medline:
2
6
2024
pubmed:
2
6
2024
entrez:
1
6
2024
Statut:
epublish
Résumé
Structural biology is solving an ever-increasing number of snapshots of ion channel conformational ensembles. Deciphering ion channel mechanisms, however, requires understanding the ensemble dynamics beyond the static structures. Here, we present a molecular modeling-based approach characterizing the ion channel structural intermediates, or their "dynamic molecular portraits", by assessing water and ion conductivity along with the detailed evaluation of pore hydrophobicity and residue packing. We illustrate the power of this approach by analyzing structures of few vanilloid-subfamily transient receptor potential (TRPV) channels. Based on the pore architecture, there are three major states that are common for TRPVs, which we call α-closed, π-closed, and π-open. We show that the pore hydrophobicity and residue packing for the open state is most favorable for the pore conductance. On the contrary, the α-closed state is the most hydrophobic and always non-conducting. Our approach can also be used for structural and functional classification of ion channels.
Identifiants
pubmed: 38824263
doi: 10.1038/s42004-024-01198-z
pii: 10.1038/s42004-024-01198-z
doi:
Types de publication
Journal Article
Langues
eng
Pagination
119Subventions
Organisme : Russian Science Foundation (RSF)
ID : 23-14-00313
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 464295817
Organisme : NIAMS NIH HHS
ID : R01 AR078814
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206573
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS083660
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS107253
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Lau, C. et al. Never at rest: insights into the conformational dynamics of ion channels from cryo-electron microscopy. J. Physiol. 596, 1107 (2018).
pubmed: 29377132
pmcid: 5878226
doi: 10.1113/JP274888
Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517 (2003).
pubmed: 14654832
doi: 10.1038/nature02196
Nilius B., Flockerzi V. Handbook of Experimental Pharmacology, 223 (Springer, 2014)
Morales-Lazaro, S. L., Lemus, L. & Rosenbaum, T. Regulation of thermoTRPs by lipids. Temperature 4, 24 (2017).
doi: 10.1080/23328940.2016.1254136
Pumroy, R. A., Fluck, E. C., Ahmed, T. & Moiseenkova-Bell, V. Y. Structural insights into the gating mechanisms of TRPV channels. Cell Calcium 87, 102168 (2020).
pubmed: 32004816
pmcid: 7153993
doi: 10.1016/j.ceca.2020.102168
Lansky, S. et al. A pentameric TRPV3 channel with a dilated pore. Nature 621, 206 (2023).
pubmed: 37648856
pmcid: 10584365
doi: 10.1038/s41586-023-06470-1
Rao, S. et al. Water and hydrophobic gates in ion channels and nanopores. Faraday Discuss. 209, 231 (2018).
pubmed: 29969132
pmcid: 6161260
doi: 10.1039/C8FD00013A
Huffer, K. E. et al. Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms. eLife 9, 58660 (2020).
doi: 10.7554/eLife.58660
Klesse, G., Rao, S., Sansom, M. S. P. & Tucker, S. J. CHAP: a versatile tool for the structural and functional annotation of ion channel pores. J. Mol. Biol. 431, 3353 (2019).
pubmed: 31220459
pmcid: 6699600
doi: 10.1016/j.jmb.2019.06.003
Zubcevic, L. & Lee, S.-Y. The role of π-helices in TRP channel gating. Curr. Opin. Struct. Biol. 58, 314 (2019).
pubmed: 31378426
pmcid: 6778516
doi: 10.1016/j.sbi.2019.06.011
McGoldrick, L. et al. Opening of the human epithelial calcium channel TRPV6. Nature 553, 233 (2018).
pubmed: 29258289
doi: 10.1038/nature25182
Lubova, K. I. et al. Probing temperature and capsaicin-induced activation of TRPV1 channel via computationally guided point mutations in its pore and TRP domains. Int. J. Biol. Macromol. 158, 1175 (2020).
doi: 10.1016/j.ijbiomac.2020.04.239
Zheng, W. et al. Identification and characterization of hydrophobic gate residues in TRP channels. FASEB J. 32, 639–653 (2018).
pubmed: 28970257
doi: 10.1096/fj.201700599RR
Zhang, K., Julius, D. & Cheng, Y. Structural snapshots of TRPV1 reveal mechanism of polymodal functionality. Cell 184, 1–13 (2021).
doi: 10.1016/j.cell.2021.08.012
Nadezhdin, K. D. et al. Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel. Nat. Struct. Mol. Biol. 28, 564 (2021).
pubmed: 34239124
pmcid: 8283911
doi: 10.1038/s41594-021-00615-4
Kasimova, M. A. et al. A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine. J. Gen. Physiol. 150, 1554 (2018).
pubmed: 30333107
pmcid: 6219692
doi: 10.1085/jgp.201812124
Cao, E. Structural mechanisms of transient receptor potential ion channels. J. Gen. Physiol. 152, e201811998 (2020).
pubmed: 31972006
pmcid: 7054860
doi: 10.1085/jgp.201811998
Singh, A. K. et al. Structural basis of temperature sensation by the TRP channel TRPV3. Nat. Struct. Mol. Biol. 26, 994 (2019).
pubmed: 31636415
pmcid: 6858569
doi: 10.1038/s41594-019-0318-7
Bhardwaj, R. et al. Inactivation-mimicking block of the epithelial calcium channel TRPV6. Sci. Adv. 6, 1508 (2020).
doi: 10.1126/sciadv.abe1508
Neuberger, A., Nadezhdin, K. D. & Sobolevsky, A. I. Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole. Nat. Commun. 12, 6284 (2021).
pubmed: 34725357
pmcid: 8560856
doi: 10.1038/s41467-021-26608-x
Efremov, R. G. Dynamic “molecular portraits” of biomembranes drawn by their lateral nanoscale inhomogeneities. Int. J. Mol. Sci. 22, 6250 (2021).
pubmed: 34200697
pmcid: 8230387
doi: 10.3390/ijms22126250
Efremov, R. G. et al. Molecular lipophilicity in protein modeling and drug design. Curr. Med. Chem. 14, 393 (2007).
pubmed: 17305542
doi: 10.2174/092986707779941050
Koromyslova, A. D., Chugunov, A. O. & Efremov, R. G. Deciphering fine molecular details of proteins’ structure and function with a Protein Surface Topography (PST) method. J. Chem. Inf. Model. 54, 1189 (2014).
pubmed: 24689707
doi: 10.1021/ci500158y
Chugunov, A. et al. Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains. Sci. Rep. 6, 33112 (2016).
pubmed: 27612191
pmcid: 5017144
doi: 10.1038/srep33112
Eisenberg, D., Lüthy, R. & Bowie, J. U. VERIFY3D: assessment of protein models with three-dimensional profiles. Methods Enzymol. 277, 396 (1997).
pubmed: 9379925
doi: 10.1016/S0076-6879(97)77022-8
Bowie, J. U., Lüthy, R. & Eisenberg, D. A method to identify protein sequences that fold into a known three-dimensional structure. Science 253, 164–170 (1991).
pubmed: 1853201
doi: 10.1126/science.1853201
Clapham, D. E. & Miller, C. A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc. Natl Acad. Sci. USA 108, 19492 (2011).
pubmed: 22109551
pmcid: 3241781
doi: 10.1073/pnas.1117485108
Nadezhdin, K. D. et al. TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site. Sci. Adv.10, eadn2453 (2024).
pubmed: 38691614
pmcid: 11062575
doi: 10.1126/sciadv.adn2453
Singh, A. K., McGoldrick, L. L. & Sobolevsky, A. I. Structure and gating mechanism of the transient receptor potential channel TRPV3. Nat. Struct. Mol. Biol. 25, 805 (2018).
pubmed: 30127359
pmcid: 6128766
doi: 10.1038/s41594-018-0108-7
Deng, Z. et al. Gating of human TRPV3 in a lipid bilayer. Nat. Struct. Mol. Biol. 27, 635 (2020).
pubmed: 32572252
pmcid: 7354234
doi: 10.1038/s41594-020-0428-2
Yonkunas, M. & Kurnikova, M. The hydrophobic effect contributes to the closed state of a simplified ion channel through a conserved hydrophobic patch at the pore-helix crossing. Front. Pharmacol. 6, 284 (2015).
pubmed: 26640439
pmcid: 4661268
doi: 10.3389/fphar.2015.00284
Nadezhdin, K. D. et al. Structure of human TRPV4 in complex with GTPase RhoA. Nat. Commun. 14, 3733 (2023).
pubmed: 37353478
pmcid: 10290124
doi: 10.1038/s41467-023-39346-z
Nadezhdin, K. D. et al. Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nat. Commun. 12, 2154 (2021).
pubmed: 33846324
pmcid: 8041747
doi: 10.1038/s41467-021-22507-3
Pumroy, R. A. et al. Molecular mechanism of TRPV2 channel modulation by cannabidiol. eLife 8, 48792 (2019).
doi: 10.7554/eLife.48792
Pumroy, R. A. et al. Structural insights into TRPV2 activation by small molecules. Nat. Commun. 13, 2334 (2022).
pubmed: 35484159
pmcid: 9051106
doi: 10.1038/s41467-022-30083-3
Dosey, T. L. et al. Structures of TRPV2 in distinct conformations provide insight into role of the pore turret. Nat. Struct. Mol. Biol. 26, 40 (2019).
pubmed: 30598551
doi: 10.1038/s41594-018-0168-8
Zhen Su, N. et al. Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands. Nat. Chem. Biol. 19, 72 (2023).
doi: 10.1038/s41589-022-01139-8
Kwon, D. H. et al. TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease. Nat. Commun. 14, 3732 (2023).
pubmed: 37353484
pmcid: 10290081
doi: 10.1038/s41467-023-39345-0
Fluck, E. C., Yazici, A. T., Rohacs, T. & Moiseenkova-Bell, V. Y. Structural basis of TRPV5 regulation by physiological and pathophysiological modulators. Cell Rep. 39, 110737 (2022).
pubmed: 35476976
pmcid: 9088182
doi: 10.1016/j.celrep.2022.110737
Hughes, T. E. T. et al. Structural insights on TRPV5 gating by endogenous modulators. Nat. Commun. 9, 4198 (2018).
pubmed: 30305626
pmcid: 6179994
doi: 10.1038/s41467-018-06753-6
Dang, S. et al. Structural insight into TRPV5 channel function and modulation. Proc. Natl Acad. Sci. USA 116, 8869 (2019).
pubmed: 30975749
pmcid: 6500171
doi: 10.1073/pnas.1820323116
Neuberger, A. et al. Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein. Nat. Commun. 14, 2659 (2023).
pubmed: 37160865
pmcid: 10169861
doi: 10.1038/s41467-023-38352-5
Nordquist, E. B., Schultz, S. A. & Chen, J. Using metadynamics to explore the free energy of dewetting in biologically relevant nanopores. J. Phys. Chem. B 126, 6428 (2022).
pubmed: 35998613
pmcid: 9932947
doi: 10.1021/acs.jpcb.2c04157
Trofimov, Y. A., Krylov, N. A. & Efremov, R. G. Confined dynamics of water in transmembrane pore of TRPV1 ion channel. Int J. Mol. Sci. 20, 4285 (2019).
pubmed: 31480555
pmcid: 6747475
doi: 10.3390/ijms20174285
Kasimova, M. et al. Ion Channel sensing: are fluctuations the crux of the matter? J. Phys. Chem. Lett. 9, 1260 (2018).
pubmed: 29439562
pmcid: 6310152
doi: 10.1021/acs.jpclett.7b03396
Trofimov Y. A., Minakov A. S., Krylov N. A., Efremov R. G. Structural mechanism of ionic conductivity of the TRPV1 channel. Dokl Biochem. Biophys. https://doi.org/10.1134/S1607672922600245 (2023)
Lee, C. H. & MacKinnon, R. Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures. Science 360, 508–513 (2018).
pubmed: 29724949
pmcid: 6241251
doi: 10.1126/science.aas9466
Rohaim, A. et al. Open and closed structures of a barium-blocked potassium channel. J. Mol. Biol. 432, 4783–4798 (2020).
pubmed: 32615129
pmcid: 7453360
doi: 10.1016/j.jmb.2020.06.012
Twomey, E. et al. Channel opening and gating mechanism in AMPA-subtype glutamate receptors. Nature 549, 60 (2017).
pubmed: 28737760
pmcid: 5743206
doi: 10.1038/nature23479
Rao, S. et al. A heuristic derived from analysis of the ion channel structural proteome permits the rapid identification of hydrophobic gates. Proc. Natl Acad. Sci. USA 116, 13989 (2019).
pubmed: 31235590
pmcid: 6628796
doi: 10.1073/pnas.1902702116
Lynch, C. I. et al. Water nanoconfined in a hydrophobic pore: molecular dynamics simulations of transmembrane protein 175 and the influence of water models. ACS Nano 15, 19098 (2021).
pubmed: 34784172
pmcid: 7612143
doi: 10.1021/acsnano.1c06443
Xenakis, M. N. et al. Cumulative hydropathic topology of a voltage-gated sodium channel at atomic resolution. Proteins 88, 1319 (2020).
pubmed: 32447794
doi: 10.1002/prot.25951
Marks, C. & Deane, C. M. Increasing the accuracy of protein loop structure prediction with evolutionary constraints. Bioinformatics 35, 2585 (2019).
pubmed: 30535347
doi: 10.1093/bioinformatics/bty996
Jurrus, E. et al. Improvements to the APBS biomolecular solvation software suite. Prot. Sci. 27, 112 (2018).
doi: 10.1002/pro.3280
Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1, 19 (2015).
doi: 10.1016/j.softx.2015.06.001
Lindorff-Larsen, K. et al. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 8, 1950 (2010).
doi: 10.1002/prot.22711
Jorgensen, W. L. & Tirado-Rives, J. Potential energy functions for atomic-level simulations of water and organic and biomolecular systems. Proc. Natl Acad. Sci. USA 102, 6665 (2005).
pubmed: 15870211
pmcid: 1100738
doi: 10.1073/pnas.0408037102
Hess, B., Bekker, H., Berendsen, H. J. C. & Fraaije, J. G. E. M. LINCS: a linear constraint solver for molecular simulations. J. Comp. Chem. 18, 1463 (1997).
doi: 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H
Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089 (1993).
doi: 10.1063/1.464397
Joung, I. S. & Cheatham, T. E. Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. J. Phys. Chem. B 30, 9020 (2008).
doi: 10.1021/jp8001614
Li, P., Roberts, B. P., Chakravorty, D. K. & Merz, K. M. Jr. Rational design of particle mesh ewald compatible lennard-jones parameters for +2 metal cations in explicit solvent. J. Chem. Theory Comput. 9, 2733 (2013).
pubmed: 23914143
pmcid: 3728907
doi: 10.1021/ct400146w
Ghose, A. K., Viswanadhan, V. N. & Wendoloski, J. J. Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: an analysis of ALOGP and CLOGP methods. J. Phys. Chem. A 102, 3762 (1998).
doi: 10.1021/jp980230o
Wildman, S. A. & Crippen, G. M. Prediction of physicochemical parameters by atomic contributions. J. Chem. Inf. Comput. Sci. 39, 868 (1999).
doi: 10.1021/ci990307l
Amanatides J., Woo A. A fast voxel traversal algorithm for ray tracing. Eurographics https://doi.org/10.2312/egtp.19871000 (1987).
Goldstein, R. A. & Nagel, R. 3-D Visual simulation. Simulation 16, 25–31 (1971).
doi: 10.1177/003754977101600104
Roth, S. D. Ray casting for modeling solids. Comp. Graph Im. Proc. 18, 109 (1982).
doi: 10.1016/0146-664X(82)90169-1
Connolly, M. L. Analytical molecular surface calculation. J. Appl Cryst. 16, 548–558 (1983).
doi: 10.1107/S0021889883010985
Smart, O. S., Goodfellow, J. M. & Wallace, B. A. The pore dimensions of gramicidin A. Biophys. J. 65, 2455 (1993).
pubmed: 7508762
pmcid: 1225986
doi: 10.1016/S0006-3495(93)81293-1