Pre-catalytic activation pathway of the Smc5/6 complex

Abstract

The Smc5/6 complex (Smc5/6) preserves genome stability through ATP-dependent DNA organization, but the structural details that prime the complex for productive DNA engagement remain unknown. Here, we combine cryo-electron microscopy and conformational heterogeneity analysis to define the pre-catalytic activation pathway of Smc5/6. We show that in the absence of ATP and DNA, Smc5/6 exists as a heterogeneous conformational ensemble composed predominantly of two conformations termed Bridge and Cross. In the presence of DNA alone, Smc5/6 adopts a Juxtaposed conformation that brings the ATPase heads into proximity, aligning them for nucleotide engagement. With both ATP and DNA associated, Smc5/6 establishes an Engaged architecture, within which DNA stabilizes its head-associated binding cavity through local remodeling of the complex. Conformational heterogeneity analyses suggest a continuous structural transition between the Cross and Juxtaposed states, while anisotropic network modeling identifies the Bridge-Cross-Juxtaposed-Engaged sequence as the mechanically favored pathway connecting the four experimentally observed conformations. Together, these findings support a pre-catalytic conformational pathway for Smc5/6 activation and provide a structural framework for understanding how conformational heterogeneity gives rise to an activation-competent motor state.

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BibTeX RIS

BibTeX

@misc{wong2026precatalytic,
  title = {{Pre-catalytic activation pathway of the Smc5/6 complex}},
  author = {J. S. K. Wong and M. S. Loke and B. Pradhan and T. Kanno and C. Björkegren and E. Kim},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.09.757879},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757879v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Pre-catalytic activation pathway of the Smc5/6 complex
AU  - J. S. K. Wong
AU  - M. S. Loke
AU  - B. Pradhan
AU  - T. Kanno
AU  - C. Björkegren
AU  - E. Kim
PY  - 2026
DA  - 2026/10/09
PB  - bioRxiv
DO  - 10.64898/2026.10.09.757879
UR  - https://www.biorxiv.org/content/10.64898/2026.10.09.757879v1
AB  - The Smc5/6 complex (Smc5/6) preserves genome stability through ATP-dependent DNA organization, but the structural details that prime the complex for productive DNA engagement remain unknown. Here, we combine cryo-electron microscopy and conformational heterogeneity analysis to define the pre-catalytic activation pathway of Smc5/6. We show that in the absence of ATP and DNA, Smc5/6 exists as a heterogeneous conformational ensemble composed predominantly of two conformations termed Bridge and Cross. In the presence of DNA alone, Smc5/6 adopts a Juxtaposed conformation that brings the ATPase heads into proximity, aligning them for nucleotide engagement. With both ATP and DNA associated, Smc5/6 establishes an Engaged architecture, within which DNA stabilizes its head-associated binding cavity through local remodeling of the complex. Conformational heterogeneity analyses suggest a continuous structural transition between the Cross and Juxtaposed states, while anisotropic network modeling identifies the Bridge-Cross-Juxtaposed-Engaged sequence as the mechanically favored pathway connecting the four experimentally observed conformations. Together, these findings support a pre-catalytic conformational pathway for Smc5/6 activation and provide a structural framework for understanding how conformational heterogeneity gives rise to an activation-competent motor state.
ER  -

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