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TitleCryo-EM, Protein Engineering, and Simulation Enable the Development of Peptide Therapeutics against Acute Myeloid Leukemia.
Journal, issue, pagesACS Cent Sci, Vol. 8, Issue 2, Page 214-222, Year 2022
Publish dateFeb 23, 2022
AuthorsKaiming Zhang / Naoki Horikoshi / Shanshan Li / Alexander S Powers / Mikhail A Hameedi / Grigore D Pintilie / Hee-Don Chae / Yousuf A Khan / Carl-Mikael Suomivuori / Ron O Dror / Kathleen M Sakamoto / Wah Chiu / Soichi Wakatsuki /
PubMed AbstractCryogenic electron microscopy (cryo-EM) has emerged as a viable structural tool for molecular therapeutics development against human diseases. However, it remains a challenge to determine structures ...Cryogenic electron microscopy (cryo-EM) has emerged as a viable structural tool for molecular therapeutics development against human diseases. However, it remains a challenge to determine structures of proteins that are flexible and smaller than 30 kDa. The 11 kDa KIX domain of CREB-binding protein (CBP), a potential therapeutic target for acute myeloid leukemia and other cancers, is a protein which has defied structure-based inhibitor design. Here, we develop an experimental approach to overcome the size limitation by engineering a protein double-shell to sandwich the KIX domain between apoferritin as the inner shell and maltose-binding protein as the outer shell. To assist homogeneous orientations of the target, disulfide bonds are introduced at the target-apoferritin interface, resulting in a cryo-EM structure at 2.6 Å resolution. We used molecular dynamics simulations to design peptides that block the interaction of the KIX domain of CBP with the intrinsically disordered pKID domain of CREB. The double-shell design allows for fluorescence polarization assays confirming the binding between the KIX domain in the double-shell and these interacting peptides. Further cryo-EM analysis reveals a helix-helix interaction between a single KIX helix and the best peptide, providing a possible strategy for developments of next-generation inhibitors.
External linksACS Cent Sci / PubMed:35233453 / PubMed Central
MethodsEM (single particle)
Resolution2.3 - 2.57 Å
Structure data

EMDB-25791:
cryo-EM structure of MBP-KIX-apoferritin
Method: EM (single particle) / Resolution: 2.57 Å

EMDB-25799:
cryo-EM structure of MBP-KIX-apoferritin complex with peptide 7
Method: EM (single particle) / Resolution: 2.3 Å

Source
  • Homo sapiens (human)

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