5UR7

Crystal structure of engineered CCL20 disulfide locked dimer

Summary for 5UR7

• Entry DOI: 10.2210/pdb5ur7/pdb
• Descriptor: C-C motif chemokine 20, ACETATE ION, ISOPROPYL ALCOHOL, ... (4 entities in total)
• Functional Keywords: ccl20, chemokine, macrophage inflammatory protein-3 alpha, mip3-alpha, chemotaxis, psoriasis, locked dimer, cytokine, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 16474.58

Authors

Getschman, A.E.,Peterson, F.C.,Volkman, B.F. (deposition date: 2017-02-09, release date: 2017-11-22, Last modification date: 2024-10-23)

Primary citation

Getschman, A.E.,Imai, Y.,Larsen, O.,Peterson, F.C.,Wu, X.,Rosenkilde, M.M.,Hwang, S.T.,Volkman, B.F.
Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model.
Proc. Natl. Acad. Sci. U.S.A., 114:12460-12465, 2017

PubMed Abstract: Psoriasis is a chronic inflammatory skin disease characterized by the infiltration of T cell and other immune cells to the skin in response to injury or autoantigens. Conventional, as well as unconventional, γδ T cells are recruited to the dermis and epidermis by CCL20 and other chemokines. Together with its receptor CCR6, CCL20 plays a critical role in the development of psoriasiform dermatitis in mouse models. We screened a panel of CCL20 variants designed to form dimers stabilized by intermolecular disulfide bonds. A single-atom substitution yielded a CCL20 variant (CCL20 S64C) that acted as a partial agonist for the chemokine receptor CCR6. CCL20 S64C bound CCR6 and induced intracellular calcium release, consistent with G-protein activation, but exhibited minimal chemotactic activity. Instead, CCL20 S64C inhibited CCR6-mediated T cell migration with nominal impact on other chemokine receptor signaling. When given in an IL-23-dependent mouse model for psoriasis, CCL20 S64C prevented psoriatic inflammation and the up-regulation of IL-17A and IL-22. Our results validate CCR6 as a tractable therapeutic target for psoriasis and demonstrate the value of CCL20 S64C as a lead compound.

PubMed: 29109267
DOI: 10.1073/pnas.1704958114

Experimental method

X-RAY DIFFRACTION (2.0004 Å)