View source for 9sic


==Crystal structure of human Signal Regulatory Protein 2 (SIRP) alpha V2 - Q52A mutant==
<StructureSection load='9sic' size='340' side='right'caption='[[9sic]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9sic]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9SIC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SIC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9sic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9sic OCA], [https://pdbe.org/9sic PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9sic RCSB], [https://www.ebi.ac.uk/pdbsum/9sic PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9sic ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The protein-protein interaction between Signal Regulatory Protein alpha (SIRPalpha) 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 SIRPalpha 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 combination of NMR spectroscopy, molecular dynamics simulations, and biophysical assays, we demonstrate that access to this cryptic site is dynamically controlled by a single "gatekeeper" residue, Gln52. The rotameric state of Gln52 dictates a conformational equilibrium between a "closed," state and a ligand-accessible "open" state. We validated this mechanism by engineering SIRPalpha mutants to bias this equilibrium. A Q52F mutation locked the pocket in a closed state, abolishing both CD47 and fragment binding, while Q52A and Q52R mutations biased the protein toward an open state. These "open-biased" mutants not only exhibited decreased affinity for CD47 but also significantly improved binding to small-molecule fragments that inhibit the SIRPalpha-CD47 interaction. This work reveals the intrinsic conformational plasticity of SIRPalpha and establishes a validated structure-based roadmap for a new class of allosteric inhibitors. This 'flexibility-for-inhibition' strategy functions by trapping a non-binding conformation and represents a broadly applicable framework for targeting this and other challenging immune checkpoints.

Engineering SIRPalpha conformational plasticity to reveal a cryptic pocket suitable for structure-based drug design.,Storder M, Barelier S, Cordier F, Yacoub T, Ilari L, Barral K, Mahmoodi S, Saez-Ayala M, Combes S, Betzi S, Derviaux C, Ulliana A, Torres F, Rubin J, Roche P, Morelli X, Garcin ED, Miller TW bioRxiv [Preprint]. 2025 Dec 23:2025.12.10.693509. doi: , 10.64898/2025.12.10.693509. PMID:41497624<ref>PMID:41497624</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9sic" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Barelier S]]
[[Category: Betzi S]]
[[Category: Garcin ED]]
[[Category: Miller TW]]