Engineering SIRPα conformational plasticity to reveal a cryptic pocket suitable for structure-based drug design.

ABSTRACT: The protein-protein interaction between Signal Regulatory Protein alpha (SIRPα) and CD47 is a critical immune checkpoint that enables tumor immune escape, making it a key target for cancer immunotherapy. While antibody-based therapies exist, the development of small-molecule inhibitors has been hindered by the flat, featureless binding interface. Here, we report the discovery of a novel, druggable cryptic pocket within the SIRPα D1 domain (the WYF pocket), revealed through a structure-based fragment screening campaign using x-ray crystallography. This pocket, defined by residues Trp38, Tyr50, and Phe74, is only accessible in a conformation that is incompatible with CD47 binding, making it a candidate for structure-based drug design and immune checkpoint inhibitor development. Through a com

SUBMITTER: Storder M 

PROVIDER: S-EPMC12767662 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature