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9mhx

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Human TLR8 ectodomain with small molecule agonist 7

Structural highlights

9mhx is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.13Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TLR8_HUMAN Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.^[1]

Publication Abstract from PubMed

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure-activity relationship studies guided by structure-based drug design are described.

Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach.,Poudel YB, Lo JC, Norris DJ, Cox M, He L, Johnson WL, A M Subbaiah M, Mondal S, Thangavel S, Subramani L, Reddy M, Jain S, Weiss DR, Sivaprakasam P, Critton D, Mulligan D, Xie C, Dhar P, Li Y, Sega E, Yamazoe S, Gavai AV, Mathur A, Zapf CW, Chekler EP ACS Med Chem Lett. 2024 Dec 19;16(1):80-88. doi: 10.1021/acsmedchemlett.4c00463. , eCollection 2025 Jan 9. PMID:39811121^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Doyle SL, Jefferies CA, Feighery C, O'Neill LA. Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase. J Biol Chem. 2007 Dec 21;282(51):36953-60. Epub 2007 Oct 11. PMID:17932028 doi:10.1074/jbc.M707682200
↑ Poudel YB, Lo JC, Norris DJ, Cox M, He L, Johnson WL, A M Subbaiah M, Mondal S, Thangavel S, Subramani L, Reddy M, Jain S, Weiss DR, Sivaprakasam P, Critton D, Mulligan D, Xie C, Dhar P, Li Y, Sega E, Yamazoe S, Gavai AV, Mathur A, Zapf CW, Chekler EP. Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach. ACS Med Chem Lett. 2024 Dec 19;16(1):80-88. PMID:39811121 doi:10.1021/acsmedchemlett.4c00463