Solution structures of human LL-37 fragments and NMR-based identification of a minimal membrane-targeting antimicrobial and anticancer region

Journal of the American Chemical Society
Xia LiGuangshun Wang

Abstract

To understand the structure and activity relationship of human LL-37, a series of peptide fragments was designed. The N-terminal fragment, LL-37(1-12), was not active, while the C-terminal fragment, LL-37(13-37), killed Escherichia coli, as well as drug-sensitive and drug-resistant cancer cells. A 13-residue core antibacterial and anticancer peptide, corresponding to residues 17-29 of LL-37, was identified based on total correlated spectroscopy by trimming nonessential regions (TOCSY-trim). Because LL-37 acts on bacterial membranes, three-dimensional structures of its fragments were determined in micelles by NMR, including structural refinement by natural abundance 15N and 13C chemical shifts. Aromatic-aromatic interactions in the N-terminal fragment were proposed to be essential for LL-37 aggregation. The LL-37 core peptide adopts a similar structure in the micelles of SDS or dioctanoyl phosphatidylglycerol. This structure is retained in the C-terminal fragment LL-37(13-37) and very likely in intact LL-37 based on peptide-aided signal assignments. The higher antibacterial activity of the LL-37 core peptide than aurein 1.2 was attributed to additional cationic residues. To achieve selective membrane targeting, D-amino acids wer...Continue Reading

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Citations

Jan 6, 2010·Archivum Immunologiae Et Therapiae Experimentalis·Robert BuckiWojciech Sokołowski
Jul 19, 2012·Journal of the American Chemical Society·Biswajit Mishra, Guangshun Wang
Oct 30, 2008·Nucleic Acids Research·Guangshun WangZhe Wang
Jul 8, 2009·Antimicrobial Agents and Chemotherapy·Raquel F EpandRichard M Epand
Jul 2, 2008·Antimicrobial Agents and Chemotherapy·Guangshun WangRobert W Buckheit
Nov 16, 2011·Antimicrobial Agents and Chemotherapy·Guangshun WangRichard M Epand
Feb 22, 2011·Applied and Environmental Microbiology·Imma GüellEmilio Montesinos
Jan 6, 2009·Ophthalmic Research·Alison M McDermott
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May 16, 2014·Pharmaceuticals·Guangshun Wang
May 21, 2011·Cellular and Molecular Life Sciences : CMLS·Andrea Giuliani, Andrea C Rinaldi
Mar 26, 2015·Pharmaceuticals·Guangshun WangXiuqing Wang
Feb 16, 2016·Biochimica Et Biophysica Acta·Xianwei ZhangThomas Vorup-Jensen
Jan 29, 2016·ACS Medicinal Chemistry Letters·Biswajit MishraGuangshun Wang
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