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Crystal Structures of Stapled and Hydrogen Bond Surrogate Peptides Targeting a Fully Buried Protein–Helix Interaction

DOI: 10.1021/cb500271c DOI Help
PMID: 25084543 PMID Help

Authors: Christopher Douse (Department of Chemistry, Imperial College London, U.K.) , Sabrina J. Maas (Department of Chemistry, Imperial College London, U.K.) , Jemima C. Thomas (Department of Chemistry, Imperial College London, U.K.) , James Garnett (Centre for Structural Biology, Imperial College London, U.K.) , Yunyun Sun (Department of Chemistry, Imperial College London, U.K.) , Ernesto Cota (Centre for Structural Biology, Imperial College London, U.K.) , Edward W. Tate (Department of Chemistry, Imperial College London, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: ACS Chemical Biology , VOL 9 (10) , PAGES 2204–2209

State: Published (Approved)
Published: August 2014
Diamond Proposal Number(s): 9424

Open Access Open Access

Abstract: Constrained alpha-helical peptides are an exciting class of molecule designed to disrupt protein-protein interactions (PPIs) at a surface-exposed helix binding site. Complexes that engage more than one helical face account for over a third of structurally characterized helix PPIs, including several examples where the helix is fully buried. However, no constrained peptides have been reported that have targeted this class of interaction. We report the design of stapled and hydrogen bond surrogate (HBS) peptides mimicking the helical tail of the malaria parasite invasion motor myosin (myoA), which presents polar and hydrophobic functionality on all three faces in binding its partner, myoA tail interacting protein (MTIP), with high affinity. The first structures of these different constrained peptides bound to the same target are reported, enabling a direct comparison between these constraints and between staples based on monosubstituted pentenyl glycine (pGly) and disubstituted pentenyl alanine (pAla). Importantly, installation of these constraints does not disrupt native interactions in the buried site, so the affinity of the wild-type peptide is maintained.

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 24/09/2014 16:52

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