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Retrieving functional pathways of biomolecules from single-particle snapshots

Author

Listed:
  • Ali Dashti

    (University of Wisconsin Milwaukee)

  • Ghoncheh Mashayekhi

    (University of Wisconsin Milwaukee)

  • Mrinal Shekhar

    (University of Illinois at Urbana-Champaign 405 N. Mathews Ave.
    Arizona State University)

  • Danya Ben Hail

    (City University of New York)

  • Salah Salah

    (City University of New York
    City College of New York
    The Graduate Center of the City University of New York)

  • Peter Schwander

    (University of Wisconsin Milwaukee)

  • Amedee des Georges

    (City University of New York
    City College of New York
    The Graduate Center of the City University of New York)

  • Abhishek Singharoy

    (Arizona State University)

  • Joachim Frank

    (Columbia University
    Columbia University)

  • Abbas Ourmazd

    (University of Wisconsin Milwaukee)

Abstract

A primary reason for the intense interest in structural biology is the fact that knowledge of structure can elucidate macromolecular functions in living organisms. Sustained effort has resulted in an impressive arsenal of tools for determining the static structures. But under physiological conditions, macromolecules undergo continuous conformational changes, a subset of which are functionally important. Techniques for capturing the continuous conformational changes underlying function are essential for further progress. Here, we present chemically-detailed conformational movies of biological function, extracted data-analytically from experimental single-particle cryo-electron microscopy (cryo-EM) snapshots of ryanodine receptor type 1 (RyR1), a calcium-activated calcium channel engaged in the binding of ligands. The functional motions differ substantially from those inferred from static structures in the nature of conformationally active structural domains, the sequence and extent of conformational motions, and the way allosteric signals are transduced within and between domains. Our approach highlights the importance of combining experiment, advanced data analysis, and molecular simulations.

Suggested Citation

  • Ali Dashti & Ghoncheh Mashayekhi & Mrinal Shekhar & Danya Ben Hail & Salah Salah & Peter Schwander & Amedee des Georges & Abhishek Singharoy & Joachim Frank & Abbas Ourmazd, 2020. "Retrieving functional pathways of biomolecules from single-particle snapshots," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18403-x
    DOI: 10.1038/s41467-020-18403-x
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    Cited by:

    1. Bintao He & Fa Zhang & Chenjie Feng & Jianyi Yang & Xin Gao & Renmin Han, 2024. "Accurate global and local 3D alignment of cryo-EM density maps using local spatial structural features," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Marco C. Miotto & Steven Reiken & Anetta Wronska & Qi Yuan & Haikel Dridi & Yang Liu & Gunnar Weninger & Carl Tchagou & Andrew R. Marks, 2024. "Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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