Mechanistic insights into high mobility group box-1 (HMGb1)-induced Toll-like receptor 4 (TLR4) dimer formation

Journal of Biomolecular Structure & Dynamics
Shan SunYousef Al-Abed

Abstract

Supplemental data for this article can be accessed here.High mobility group box-1 (HMGb1), an endogenous danger-associated molecular pattern protein (DAMP) whose extracellular release has been associated with sterile injury and various inflammatory diseases and conditions, has been shown to be a valuable clinical drug target. Elucidation of the specific interactions with the HMGb1 receptor, Toll-like receptor 4 (TLR4) and adaptor protein myeloid differentiation factor-2 (MD-2), will lead to more precisely targeted therapeutics. We sought to examine detailed interactions and dynamics of the HMGb1 A-box and B-box fragments, as well as the intact protein using in silico protein-protein docking (ZDOCK, ZRANK) and molecular dynamics (Schrödinger Desmond, New York, NY). Mutagenesis and SPR-binding studies allowed us to draw further conclusions regarding the details of the HMGb1-TLR4-MD2 interaction and shed light on the reasons for the opposing biological activities of HMGb1 A-box and B-box fragments. From our findings, we hypothesize that disulfide A-box fragment binds as an anchor toward the TLR4-MD-2 but does not facilitate the TLR4 dimer formation, thereby competing with the HMGb1-binding site and preventing HMGb1-induced signali...Continue Reading

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Citations

Jun 25, 2019·Journal of Biomolecular Structure & Dynamics·Wen-Qing JiaXian-Chao Cheng
Apr 8, 2020·Experimental and Therapeutic Medicine·Jia-Zhen TangXiao-Xue Zheng
Jun 30, 2019·International Journal of Molecular Sciences·Amanda Almeida de OliveiraKenia Pedrosa Nunes
Feb 7, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Qurat Ul AinSangdun Choi
Jun 10, 2020·Computational and Structural Biotechnology Journal·Wresti L AnggayastiRicardo L Mancera
May 6, 2021·Nutrients·Roghayeh ShahbaziChantal Matar
Aug 10, 2021·Langmuir : the ACS Journal of Surfaces and Colloids·Dineli T S RanathungaSteven O Nielsen

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Methods Mentioned

BETA
surface plasmon resonance
nuclear magnetic resonance
affinity purification
chip
NMR

Software Mentioned

ZDOCK ZDOCK SERVER
ZRANK
Schrödinger Desmond Molecular Dynamics System
MOE
TASSER
ZDOCK
MOE Loop Modeler
BIAEvaluation

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