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Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance

Alexei Brooun1, Ketan S Gajiwala1, Ya-Li Deng1

  • 1Worldwide Medicinal Chemistry, Worldwide Research and Development, Pfizer Inc., San Diego, California 92121, USA.

Nature Communications
|April 29, 2016
PubMed

Insights

Polycomb repressive complex 2 (PRC2) regulates gene silencing. New crystal structures reveal how PRC2 inhibitors bind, highlighting an activation loop in EZH2 crucial for enzyme activity and drug resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator involved in gene silencing via histone H3 lysine 27 (H3K27) methylation.
  • Aberrant PRC2 activity and mutations are implicated in tumorigenesis, particularly in EZH2-mutated lymphomas.

Purpose of the Study:

  • To elucidate the molecular basis of PRC2 inhibitor recognition.
  • To understand the structural role of the EZH2 N-terminal activation loop in enzyme activity and drug resistance.

Main Methods:

  • X-ray crystallography was employed to determine the structures of wild-type and Y641N mutant PRC2 bound to inhibitors.
  • Structural analysis focused on the N-terminal region of EZH2 and its interaction with inhibitors.

Main Results:

  • The crystal structures revealed the binding mode of inhibitors to wild-type and mutant PRC2.
  • A 17-residue activation loop in EZH2 was identified as critical for stimulating enzyme activity and mediating inhibitor recognition.
  • This activation loop also plays a role in the development of drug resistance associated with PRC2 mutations.

Conclusions:

  • The identified activation loop is a key determinant of PRC2 inhibitor efficacy and resistance.
  • These findings establish a structure-based drug design platform for developing next-generation PRC2 inhibitors.

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