Crystal structure of the TLR1-TLR2-lipopeptide complex = TLR1-TLR2-지질단백질 복합체의 구조 연구

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TLR2 in complex with TLR1 or TLR6 plays an important role in innate immune response by recognizing microbial lipoproteins and lipopeptides. Here we present crystal structures of the mouse TLR2- $Pam_3 CSK_4$ (a derivative of triacylated lipopeptide) and human TLR2-TLR1- $Pam_3 CSK_4$ complexes. Binding of $Pam_3 CSK_4$ induces formation of an ``m`` shaped heterodimer of TLR1 and TLR2. Three lipid chains of $Pam_3 CSK_4$ mediate the receptor dimerization - the two ester-bound lipid chains is inserted into a pocket in TLR2 and the remaining amide bound lipid chain into a narrow channel in TLR1. Extensive hydrogen bonding network and hydrophobic interactions between TLR1 and TLR2 further stabilize the heterodimer. The ligand binding pocket of TLR2 is formed in the convex surface at the interface of the hinge and C-terminal domains. The flexible loops of LRR11 and 12 open a crevice that is connected to a large internal pocket. Hydrophobic residues from LRR9 to LRR12 modules decorate internal surface of the TLR2 pocket. The lipid binding channel of TLR1 is formed at the same area between the hinge and the C-terminal domains but is shorter and narrower than the TLR2 pocket. Modeling study suggests that TLR6 does not contain the lipid binding channel. We propose that ligandinduced dimerization of the extracellular domains of TLR family produces juxtaposed intracellular TIR domains and derives the recruitment of specific adaptor proteins through the TIR-TIR interactions for signal transduction.
Lee, Jie-Ohresearcher이지오researcher
한국과학기술원 : 화학과,
Issue Date
303662/325007  / 020045264

학위논문(박사) - 한국과학기술원 : 화학과, 2008. 8., [ xi, 117 p. ]


TLR; Hybrid LRR technique; lipopeptide; innate immunity; sepsis; 톨유사수용체; 융합 LRR 기술; 지질단백질; 선천성면역; 패혈증; TLR; Hybrid LRR technique; lipopeptide; innate immunity; sepsis; 톨유사수용체; 융합 LRR 기술; 지질단백질; 선천성면역; 패혈증

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