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Peer-reviewedCC BY-NC-NDProceedings of the National Academy of Sciences

An atlas of microtubule lattice parameters regulated through ligand binding to the microtubule-stabilizing sites

  • Daniel Lucena‐Agell1,2
  • Óscar Fernández1,3
  • Rebeca París-Ogáyar4,1,5
  • Juan Estévez‐Gallego6,7
  • Denisa Ondruskova8,9
  • Beatriz Álvarez-Bernad1,10
  • Francesca Bonato1,10
  • Jaime Larraga1,10
  • D. Ortiz de Elguea1,10
  • Gregorio Javier Cano1,10
  • Marvin Scheers1,10
  • Hiroshi Imai11,12
16 more authors
  • Toshiki Yagi13,14
  • Hiroyuki Iwamoto15,16
  • Juan Carlos Martínez-Guil17,18
  • A. Jonathan Singh19
  • Robert A. Keyzers20,21
  • Christopher D. Vanderwal22,23,24
  • Karl‐Heinz Altmann25,26
  • Johan Van der Eycken27,28
  • Valle Palomo4,5
  • Wei-Shuo Fang29,30
  • Federico Gago31,32
  • Zdeněk Lánský8,9
  • Marcus Braun8,33
  • María A. Oliva1,33
  • Shinji Kamimura34,35
  • José Fernando Díaz1,2
35 affiliations
  1. 1Unidad Interdepartamental de Desarrollo de Nuevos Fármacos Biológicos, Inmunológicos y Químicos para la Salud Global, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas
  2. 2Center for Biological Research. CSIC
  3. 3Centro de Investigaciones Biológicas Margarita Salas
  4. 4Instituto Madrileño de Estudios Avanzados en Nanociencia
  5. 5IMDEA-Nanociencia
  6. 6Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute
  7. 7Paul Scherrer Institute, Villigen,
  8. 8Institute of Biotechnology Czech Academy of Sciences, Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University
  9. 9Institute of Biotechnology of the Czech Academy of Sciences
  10. 10Centro de Investigaciones Biologicas Margarita Salas
  11. 11Department of Biological Sciences, Graduate School of Science, The University of Osaka
  12. 12Osaka University
  13. 13Department of Life Sciences, Faculty of Biological Resources, Prefectural University of Hiroshima
  14. 14Faculty of Biological Resources, Prefectural University of Hiroshima
  15. 15Research and Utilization Division, Japan Synchrotron Radiation Research Institute, SPring-8
  16. 16Japan Synchrotron Radiation Research Institute
  17. 17ALBA Synchrotron, Consorcio para la Construcción, Equipamiento y Explotación del Laboratorio de Luz de Sincrotrón
  18. 18ALBA Synchrotron, CELLS
  19. 19Ferrier Research Institute, and Centre for Biodiscovery, Victoria University of Wellington
  20. 20School of Chemical and Physical Sciences, and Centre for Biodiscovery, Victoria University of Wellington
  21. 21School of Chemical & Physical Sciences, and Centre for Biodiscovery, Victoria University of Wellington
  22. 22Department of Chemistry, 1102 Natural Sciences II, University of California
  23. 23Department of Pharmaceutical Sciences, University of California
  24. 24University of California
  25. 25ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences
  26. 26ETH Zurich
  27. 27Department of Organic and Macromolecular Chemistry, Faculty of Sciences, Ghent University
  28. 28University of Ghent
  29. 29Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  30. 30Institute of Materia Medica, Beijing
  31. 31Department of Biomedical Sciences, University of Alcalá
  32. 32Universidad de Alcala
  33. 33Institute of Biotechnology CAS, Centrum BIOCEV
  34. 34Department of Biological Sciences, Faculty of Fundamental Science and Engineering, Chuo University
  35. 35Chuo University
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Abstract

Microtubules (MTs) are dynamic cytoskeletal polymers whose lattice architecture regulates force generation, nucleotide hydrolysis, and recognition by motor proteins and microtubule-associated proteins (MAPs). Microtubule-stabilizing agents (MSAs), including taxanes and laulimalide/peloruside-site ligands, suppress depolymerization by binding to defined lattice sites, yet stabilization is not structurally neutral. How ligand chemistry reshapes lattice organization and function remains unresolved. Here, we address three mechanistic questions. First, do distinct ligand classes induce defined lattice states? Using X-ray fiber diffraction, we show that MSAs selectively stabilize two preferred longitudinal conformations, a compact state (∼4.06 nm monomer rise) and an expanded state (∼4.17 nm), while modulating lateral organization reflected in shifts in mean MT radius. These axial spacings cluster around discrete values across chemotypes, indicating stabilization of pre-existing conformational minima rather than continuous distortion. Second, are these states interconvertible upon changes in ligand occupancy? Time-resolved diffraction reveals that longitudinal transitions occur within seconds of ligand addition even at substoichiometric occupancy; whereas, lateral equilibration proceeds slower, consistent with redistribution within heterogeneous protofilament organizations. Third, do such structural states alter nucleotide hydrolysis and motor/MAP behavior? Expanded lattices are associated with reduced apparent GTP hydrolysis rates under steady-state assembly conditions and altered kinesin motility, whereas compact lattices preferentially promote tau binding and distinct motor interaction profiles. Together, these findings establish longitudinal lattice conformation as a regulatory parameter and position microtubule-stabilizing agents as chemical tools that bias a dynamic structural landscape with predictable catalytic and transport consequences. Significance statement Microtubules generate force and support intracellular transport through lattice geometries selectively recognized by motor proteins and microtubule-associated proteins. Microtubule-stabilizing drugs such as taxanes and epothilones are widely used in chemotherapy but can cause neurotoxicity, likely because stabilization alters lattice architecture rather than simply preventing depolymerization. Here, we show that stabilizing ligands bias microtubules between two preferred longitudinal conformations, compact and expanded, that can switch within seconds of binding, while lateral organization adjusts slower. These structural states differentially regulate GTP hydrolysis and recognition by tau and kinesin, linking lattice geometry to catalytic and transport functions. By establishing lattice conformation as a tunable regulatory parameter, this work provides a framework for interpreting drug effects and designing structure-selective stabilizers with improved therapeutic profiles.

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Cite

BibTeXRIS
BibTeX
@article{lucenaagell2026atlas,
  title = {{An atlas of microtubule lattice parameters regulated through ligand binding to the microtubule-stabilizing sites}},
  author = {Daniel Lucena‐Agell and Óscar Fernández and Rebeca París-Ogáyar and Juan Estévez‐Gallego and Denisa Ondruskova and Beatriz Álvarez-Bernad and Francesca Bonato and Jaime Larraga and D. Ortiz de Elguea and Gregorio Javier Cano and Marvin Scheers and Hiroshi Imai and Toshiki Yagi and Hiroyuki Iwamoto and Juan Carlos Martínez-Guil and A. Jonathan Singh and Robert A. Keyzers and Christopher D. Vanderwal and Karl‐Heinz Altmann and Johan Van der Eycken and Valle Palomo and Wei-Shuo Fang and Federico Gago and Zdeněk Lánský and Marcus Braun and María A. Oliva and Shinji Kamimura and José Fernando Díaz},
  journal = {Proceedings of the National Academy of Sciences},
  year = {2026},
  month = jun,
  doi = {10.1073/pnas.2532791123},
  url = {https://doi.org/10.1073/pnas.2532791123},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - An atlas of microtubule lattice parameters regulated through ligand binding to the microtubule-stabilizing sites
AU  - Daniel Lucena‐Agell
AU  - Óscar Fernández
AU  - Rebeca París-Ogáyar
AU  - Juan Estévez‐Gallego
AU  - Denisa Ondruskova
AU  - Beatriz Álvarez-Bernad
AU  - Francesca Bonato
AU  - Jaime Larraga
AU  - D. Ortiz de Elguea
AU  - Gregorio Javier Cano
AU  - Marvin Scheers
AU  - Hiroshi Imai
AU  - Toshiki Yagi
AU  - Hiroyuki Iwamoto
AU  - Juan Carlos Martínez-Guil
AU  - A. Jonathan Singh
AU  - Robert A. Keyzers
AU  - Christopher D. Vanderwal
AU  - Karl‐Heinz Altmann
AU  - Johan Van der Eycken
AU  - Valle Palomo
AU  - Wei-Shuo Fang
AU  - Federico Gago
AU  - Zdeněk Lánský
AU  - Marcus Braun
AU  - María A. Oliva
AU  - Shinji Kamimura
AU  - José Fernando Díaz
PY  - 2026
DA  - 2026/06/16
JO  - Proceedings of the National Academy of Sciences
DO  - 10.1073/pnas.2532791123
UR  - https://doi.org/10.1073/pnas.2532791123
AB  - Microtubules (MTs) are dynamic cytoskeletal polymers whose lattice architecture regulates force generation, nucleotide hydrolysis, and recognition by motor proteins and microtubule-associated proteins (MAPs). Microtubule-stabilizing agents (MSAs), including taxanes and laulimalide/peloruside-site ligands, suppress depolymerization by binding to defined lattice sites, yet stabilization is not structurally neutral. How ligand chemistry reshapes lattice organization and function remains unresolved. Here, we address three mechanistic questions. First, do distinct ligand classes induce defined lattice states? Using X-ray fiber diffraction, we show that MSAs selectively stabilize two preferred longitudinal conformations, a compact state (∼4.06 nm monomer rise) and an expanded state (∼4.17 nm), while modulating lateral organization reflected in shifts in mean MT radius. These axial spacings cluster around discrete values across chemotypes, indicating stabilization of pre-existing conformational minima rather than continuous distortion. Second, are these states interconvertible upon changes in ligand occupancy? Time-resolved diffraction reveals that longitudinal transitions occur within seconds of ligand addition even at substoichiometric occupancy; whereas, lateral equilibration proceeds slower, consistent with redistribution within heterogeneous protofilament organizations. Third, do such structural states alter nucleotide hydrolysis and motor/MAP behavior? Expanded lattices are associated with reduced apparent GTP hydrolysis rates under steady-state assembly conditions and altered kinesin motility, whereas compact lattices preferentially promote tau binding and distinct motor interaction profiles. Together, these findings establish longitudinal lattice conformation as a regulatory parameter and position microtubule-stabilizing agents as chemical tools that bias a dynamic structural landscape with predictable catalytic and transport consequences. Significance statement Microtubules generate force and support intracellular transport through lattice geometries selectively recognized by motor proteins and microtubule-associated proteins. Microtubule-stabilizing drugs such as taxanes and epothilones are widely used in chemotherapy but can cause neurotoxicity, likely because stabilization alters lattice architecture rather than simply preventing depolymerization. Here, we show that stabilizing ligands bias microtubules between two preferred longitudinal conformations, compact and expanded, that can switch within seconds of binding, while lateral organization adjusts slower. These structural states differentially regulate GTP hydrolysis and recognition by tau and kinesin, linking lattice geometry to catalytic and transport functions. By establishing lattice conformation as a tunable regulatory parameter, this work provides a framework for interpreting drug effects and designing structure-selective stabilizers with improved therapeutic profiles.
SN  - 0027-8424
SN  - 1091-6490
ER  -