2LMF

Solution structure of human LL-23 bound to membrane-mimetic micelles

2LMF の概要

• エントリーDOI: 10.2210/pdb2lmf/pdb
• 関連するPDBエントリー: 2K6O
• NMR情報: BMRB: 18114
• 分子名称: Antibacterial protein LL-37 (1 entity in total)
• 機能のキーワード: antimicrobial and innate immune modulating peptide, antimicrobial protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P49913
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 2831.41

構造登録者

Wang, G. (登録日: 2011-11-30, 公開日: 2011-12-28, 最終更新日: 2024-05-15)

主引用文献

Wang, G.,Elliott, M.,Cogen, A.L.,Ezell, E.L.,Gallo, R.L.,Hancock, R.E.
Structure, Dynamics, and Antimicrobial and Immune Modulatory Activities of Human LL-23 and Its Single-Residue Variants Mutated on the Basis of Homologous Primate Cathelicidins.
Biochemistry, 51:653-664, 2012

PubMed Abstract: LL-23 is a natural peptide corresponding to the 23 N-terminal amino acid residues of human host defense cathelicidin LL-37. LL-23 demonstrated, compared to LL-37, a conserved ability to induce the chemokine MCP-1 in human peripheral blood mononuclear cells, a lack of ability to suppress induction of the pro-inflammatory cytokine TNF-α in response to bacterial lipopolysaccharides (LPS), and reduced antimicrobial activity. Heteronuclear multidimensional nuclear magnetic resonance (NMR) characterization of LL-23 revealed similar secondary structures and backbone dynamics in three membrane-mimetic micelles: SDS, dodecylphosphocholine (DPC), and dioctanoylphosphatidylglycerol. The NMR structure of LL-23 determined in perdeuterated DPC contained a unique serine that segregated the hydrophobic surface of the amphipathic helix into two domains. To improve our understanding, Ser9 of LL-23was changed to either Ala or Val on the basis of homologous primate cathelicidins. These changes made the hydrophobic surface of LL-23 continuous and enhanced antibacterial activity. While identical helical structures did not explain the altered activities, a reduced rate of hydrogen-deuterium exchange from LL-23 to LL-23A9 to LL-23V9 suggested a deeper penetration of LL-23V9 into the interior of the micelles, which correlated with enhanced activities. Moreover, these LL-23 variants had discrete immunomodulatory activities. Both restored the TNF-α dampening activity to the level of LL-37. Furthermore, LL-23A9, like LL-23, maintained superior protective MCP-1 production, while LL-23V9 was strongly immunosuppressive, preventing baseline MCP-1 induction and substantially reducing LPS-stimulated MCP-1 production. Thus, these LL-23 variants, designed on the basis of a structural hot spot, are promising immune modulators that are easier to synthesize and less toxic to mammalian cells than the parent peptide LL-37.

PubMed: 22185690
DOI: 10.1021/bi2016266

実験手法

SOLUTION NMR