9KQL

The crystal structure of MORC2_CC3 domain at 3.1 Angstroms resolution

Summary for 9KQL

• Entry DOI: 10.2210/pdb9kql/pdb
• Descriptor: ATPase MORC2 (2 entities in total)
• Functional Keywords: dimer, regulation, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 24745.80

Authors

Zhang, Y.S.,Xu, W.Y.,Huang, C.D.,Wang, C. (deposition date: 2024-11-26, release date: 2025-12-03, Last modification date: 2026-06-17)

Primary citation

Zhang, Y.,Xu, W.,Duan, W.,Wei, Y.,Jiang, W.,Zhu, F.,Huang, C.,Wang, C.,Bi, Y.
MORC2 mediates transcriptional regulation through liquid-liquid phase separation.
Elife, 14:-, 2026

PubMed Abstract: MORC2 is a chromatin-associated ATPase essential for transcriptional silencing and genome stability, yet the biophysical principles governing its regulatory activity remain elusive. Here, we demonstrate that full-length MORC2 undergoes biomolecular condensation to form dynamic nuclear assemblies, a process fundamentally required for its repressor function. Endogenous MORC2 forms discrete, dynamic condensates in neurons from chimeric mice, supporting the physiological relevance of these assemblies in vivo. Mechanistically, a 3.1 Å crystal structure of coiled-coil 3 (CC3) identifies a dimeric scaffold that serves as a structural hub, while multivalent 'sticker' interactions between an intrinsically disordered region (IDR) and a newly defined IDR-binding domain (IBD) drive condensation. We show that DNA acts as a molecular scaffold that triggers MORC2 condensation, which in turn allosterically stimulates its ATPase activity. Critically, by employing a 'killswitch' strategy to decouple assembly from internal fluidity, we reveal that only dynamic MORC2 condensates, not static aggregates or condensation-deficient mutants, can restore transcriptional regulation in -knockout cells. Furthermore, pathogenic variants linked to CMT2Z and SMA differentially perturb these material properties and enzymatic turnover, providing a mechanistic link between condensate dysregulation and human neuropathies. Together, our findings establish a DNA-templated condensation mechanism for MORC2 and provide a molecular framework for understanding how the material state of chromatin-associated machinery dictates gene regulation and disease pathogenesis.

PubMed: 42160388
DOI: 10.7554/eLife.108479

Experimental method

X-RAY DIFFRACTION (3.1 Å)