Einzeltreffer — DigiBib

The chemotaxis of CD4 + type 1 helper cells and CD8 + cytotoxic lymphocytes, guided by interferon-inducible CXC chemokine 9-11 (CXCL9-11) and CXC chemokine receptor 3 (CXCR3), plays a critical role in type 1 immunity. Here we determined the structures of human CXCR3-DNG i complexes activated by chemokine CXCL11, peptidomimetic agonist PS372424 and biaryl-type agonist VUF11222, and the structure of inactive CXCR3 bound to noncompetitive antagonist SCH546738. Structural analysis revealed that PS372424 shares a similar orthosteric binding pocket to the N terminus of CXCL11, while VUF11222 buries deeper and activates the receptor in a distinct manner. We showed an allosteric binding site between TM5 and TM6, accommodating SCH546738 in the inactive CXCR3. SCH546738 may restrain the receptor at an inactive state by preventing the repacking of TM5 and TM6. By revealing the binding patterns and the pharmacological properties of the four modulators, we present the activation mechanisms of CXCR3 and provide insights for future drug development.

Titel:	Structural insights into the activation and inhibition of CXC chemokine receptor 3.
Autor/in / Beteiligte Person:	Jiao, H ; Pang, B ; Liu, A ; Chen, Q ; Pan, Q ; Wang, X ; Xu, Y ; Chiang, YC ; Ren, R ; Hu, H
Link:	View record at Springer (Volltext)
Zeitschrift:	Nature structural & molecular biology, Jg. 31 (2024-04-01), Heft 4, S. 610-620
Veröffentlichung:	New York : Nature Pub. Group, c2004-, 2024
Medientyp:	academicJournal
ISSN:	1545-9985 (electronic)
DOI:	10.1038/s41594-023-01175-5
Schlagwort:	Humans Ligands Binding Sites Protein Binding Receptors, CXCR3 metabolism Chemokines, CXC metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nat Struct Mol Biol] 2024 Apr; Vol. 31 (4), pp. 610-620. <i>Date of Electronic Publication: </i>2024 Jan 04. MeSH Terms: Receptors, CXCR3* / metabolism ; Chemokines, CXC* / metabolism ; Humans ; Ligands ; Binding Sites ; Protein Binding References: Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544. (PMID: 29872004) ; Nat Struct Mol Biol. 2022 Dec;29(12):1188-1195. (PMID: 36396979) ; Immunol Rev. 2019 May;289(1):101-114. (PMID: 30977199) ; Nat Immunol. 2021 Apr;22(4):434-448. (PMID: 33649580) ; J Biol Chem. 2008 Jul 11;283(28):19389-99. (PMID: 18411283) ; Nat Struct Mol Biol. 2018 Jun;25(6):472-481. (PMID: 29867214) ; J Chem Theory Comput. 2019 Jan 8;15(1):775-786. (PMID: 30525595) ; Nat Chem Biol. 2020 Jul;16(7):749-755. (PMID: 32483378) ; Blood. 2001 Dec 15;98(13):3554-61. (PMID: 11739156) ; J Exp Med. 1998 Jun 15;187(12):2009-21. 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Structural insights into the activation and inhibition of CXC chemokine receptor 3.