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TitleStructural basis of SIRT7 nucleosome engagement and substrate specificity.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 1328, Year 2025
Publish dateFeb 4, 2025
AuthorsCarlos Moreno-Yruela / Babatunde E Ekundayo / Polina N Foteva / Dongchun Ni / Esther Calvino-Sanles / Henning Stahlberg / Beat Fierz /
PubMed AbstractChromatin-modifying enzymes target distinct residues within histones to finetune gene expression profiles. SIRT7 is an NAD-dependent deacylase often deregulated in cancer, which deacetylates either ...Chromatin-modifying enzymes target distinct residues within histones to finetune gene expression profiles. SIRT7 is an NAD-dependent deacylase often deregulated in cancer, which deacetylates either H3 lysine 36 (H3K36) or H3K18 with high specificity within nucleosomes. Here, we report structures of nucleosome-bound SIRT7, and uncover the structural basis of its specificity towards H3K36 and K18 deacylation, combining a mechanism-based cross-linking strategy, cryo-EM, and enzymatic and cellular assays. We show that the SIRT7 N-terminus represents a unique, extended nucleosome-binding domain, reaching across the nucleosomal surface to the acidic patch. The catalytic domain binds at the H3-tail exit site, engaging both DNA gyres of the nucleosome. Contacting H3K36 versus H3K18 requires a change in binding pose, and results in structural changes in both SIRT7 and the nucleosome. These structures reveal the basis of lysine specificity, allowing us to engineer SIRT7 towards enhanced H3K18ac selectivity, and provides a basis for small molecule modulator development.
External linksNat Commun / PubMed:39900593 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.5 Å
Structure data

51449

9gmk

EMDB-51449, PDB-9gmk:
SIRT7:H3K18DTU nucleosome complex
Method: EM (single particle) / Resolution: 3.5 Å

51453

9gmr

EMDB-51453, PDB-9gmr:
SIRT7-H3K36MTUnucleosome complex
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

PDB-1iy0:
Crystal structure of the FtsH ATPase domain with AMP-PNP from Thermus thermophilus

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsDNA / nucleosome complex

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