6nih | pdb_00006nih
Crystal structure of human TLR1
Structural highlights
Function[TLR1_HUMAN] Participates in the innate immune response to microbial agents. Specifically recognizes diacylated and triacylated lipopeptides. Cooperates with TLR2 to mediate the innate immune response to bacterial lipoproteins or lipopeptides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity). Publication Abstract from PubMedDiprovocim is a recently discovered exceptionally potent, synthetic small molecule agonist of TLR2/TLR1 and has shown significant adjuvant activity in anticancer vaccination against murine melanoma. Since Diprovocim bears no structural similarity to the canonical lipopeptide ligands of TLR2/TLR1, we investigated how Diprovocim interacts with TLR2/TLR1 through in vitro biophysical, structural, and computational approaches. We found that Diprovocim induced the formation of TLR2/TLR1 heterodimers as well as TLR2 homodimers in vitro. We determined the crystal structure of Diprovocim in a complex with a TLR2 ectodomain, which revealed, unexpectedly, two Diprovocim molecules bound to the ligand binding pocket formed between two TLR2 ectodomains. Extensive hydrophobic interactions and a hydrogen-bonding network between the protein and Diprovocim molecules are observed within the defined ligand binding pocket and likely underlie the high potency of Diprovocim. Our work shed first light into the activation mechanism of TLR2/TLR1 by a noncanonical agonist. The structural information obtained here may be exploited to manipulate TLR2/TLR1-dependent signaling. Structural Basis of TLR2/TLR1 Activation by the Synthetic Agonist Diprovocim.,Su L, Wang Y, Wang J, Mifune Y, Morin MD, Jones BT, Moresco EMY, Boger DL, Beutler B, Zhang H J Med Chem. 2019 Mar 28;62(6):2938-2949. doi: 10.1021/acs.jmedchem.8b01583. Epub , 2019 Mar 13. PMID:30829478[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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