alexa Crystal structure of a self-assembling lipopeptide detergent at 1.20 A.
Pharmaceutical Sciences

Pharmaceutical Sciences

Biochemistry & Pharmacology: Open Access

Author(s): Ho DN, Pomroy NC, CuestaSeijo JA, Priv GG

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Abstract Lipopeptide detergents (LPDs) are a new class of amphiphile designed specifically for the structural study of integral membrane proteins. The LPD monomer consists of a 25-residue peptide with fatty acyl chains linked to side chains located at positions 2 and 24 of the peptide. LPDs are designed to form alpha-helices that self-assemble into cylindrical micelles, providing a more natural interior acyl chain packing environment relative to traditional detergents. We have determined the crystal structure of LPD-12, an LPD coupled to two dodecanoic acids, to a resolution of 1.20 A. The LPD-12 monomers adopt the target conformation and associate into cylindrical octamers as expected. Pairs of helices are strongly associated as Alacoil-type antiparallel dimers, and four of these dimers interact through much looser contacts into assemblies with approximate D(2) symmetry. The aligned helices form a cylindrical shell with a hydrophilic exterior that protects an interior hydrophobic cavity containing the 16 LPD acyl chains. Over 90\% of the methylene/methyl groups from the acylated side chains are visible in the micelle interiors, and approximately 90\% of these adopt trans dihedral angle conformations. Dodecylmaltoside (DDM) was required for the crystallization of LPD-12, and we find 10-24 ordered DDM molecules associated with each LPD assembly, resulting in an overall micelle molecular weight of approximately 30 kDa. The structures confirm the major design objectives of the LPD framework, and reveal unexpected features that will be helpful in the engineering additional versions of lipopeptide amphiphiles.
This article was published in Proc Natl Acad Sci U S A and referenced in Biochemistry & Pharmacology: Open Access

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