6nig

Crystal structure of the human TLR2-Diprovocim complex

spinqualitylabelsall models 6nig, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6nig is a 4 chain structure with sequence from Eptatretus stoutii and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.35Å Ligands: KQD, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TLR2_HUMAN Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 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. May also promote apoptosis in response to lipoproteins. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR6.Q2YE02_EPTST Publication Abstract from PubMed Diprovocim 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Toll-like Receptor 3D structures Variable lymphocyte receptor 3D structures

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