6LYC

Crystal structure of the NOD SIRPa complex with D4-2

Summary for 6LYC

• Entry DOI: 10.2210/pdb6lyc/pdb
• Descriptor: SIRPa of the NOD mouse strain, D4-2, ACETIC ACID, ... (4 entities in total)
• Functional Keywords: complex, cell adhesion
• Biological source: Mus musculus; More
• Total number of polymer chains: 2
• Total formula weight: 15231.00

Authors

Murata, Y.,Matsuda, M.,Nakagawa, A.,Matozaki, T. (deposition date: 2020-02-14, release date: 2020-07-01, Last modification date: 2024-11-13)

Primary citation

Hazama, D.,Yin, Y.,Murata, Y.,Matsuda, M.,Okamoto, T.,Tanaka, D.,Terasaka, N.,Zhao, J.,Sakamoto, M.,Kakuchi, Y.,Saito, Y.,Kotani, T.,Nishimura, Y.,Nakagawa, A.,Suga, H.,Matozaki, T.
Macrocyclic Peptide-Mediated Blockade of the CD47-SIRP alpha Interaction as a Potential Cancer Immunotherapy.
Cell Chem Biol, 27:1181-1191.e7, 2020

PubMed Abstract: Medium-sized macrocyclic peptides are an alternative to small compounds and large biomolecules as a class of pharmaceutics. The CD47-SIRPα signaling axis functions as an innate immune checkpoint that inhibits phagocytosis in phagocytes and has been implicated as a promising target for cancer immunotherapy. The potential of macrocyclic peptides that target this signaling axis as immunotherapeutic agents has remained unknown, however. Here we have developed a macrocyclic peptide consisting of 15 amino acids that binds to the ectodomain of mouse SIRPα and efficiently blocks its interaction with CD47 in an allosteric manner. The peptide markedly promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro as well as enhanced the inhibitory effect of anti-CD20 or anti-gp75 antibodies on tumor formation or metastasis in vivo. Our results suggest that allosteric inhibition of the CD47-SIRPα interaction by macrocyclic peptides is a potential approach to cancer immunotherapy.

PubMed: 32640189
DOI: 10.1016/j.chembiol.2020.06.008

Experimental method

X-RAY DIFFRACTION (1.36 Å)