9rob | pdb_00009rob
Crystal structure of human CD22 Ig domains 1-3 in complex with modified sialoside 1B
Structural highlights
FunctionCD22_HUMAN Mediates B-cell B-cell interactions. May be involved in the localization of B-cells in lymphoid tissues. Binds sialylated glycoproteins; one of which is CD45. Preferentially binds to alpha-2,6-linked sialic acid. The sialic acid recognition site can be masked by cis interactions with sialic acids on the same cell surface. Upon ligand induced tyrosine phosphorylation in the immune response seems to be involved in regulation of B-cell antigen receptor signaling. Plays a role in positive regulation through interaction with Src family tyrosine kinases and may also act as an inhibitory receptor by recruiting cytoplasmic phosphatases via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules. Publication Abstract from PubMedCD22 is a sialic acid-binding immunoglobulin-like lectin (Siglec) that maintains a baseline level of B cell inhibition. Its function and restricted expression in B cells make CD22 a validated target in therapies against dysregulated B cells, which cause cancer and autoimmune diseases. High-affinity sialic acid-based ligands capable of competing with natural ligands to bind CD22 represent a promising therapeutic opportunity. Here, we describe the design and synthesis of a sialoside library constructed by chemical modifications on carbon C2 of 9-N-biphenylcarboxamide Neu5Ac ((BPC)Neu5Ac) or 9-N-m-phenoxybenzamide Neu5FAc ((MPB)Neu5FAc) scaffold using a copper-(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. Subsequent analysis of binding to human CD22 using competitive binding assays and isothermal titration calorimetry reveals that addition of noncarbohydrate substituents at C2 and C9 can improve the affinity toward CD22 from high micromolar to submicromolar K (D) values. We describe the molecular basis of this affinity improvement for three of the newly synthesized compounds by solving cocrystal structures in complex with CD22. These findings contribute to our understanding of the affinity increase of chemically modified Neu5Ac toward CD22, providing the molecular basis for further compound design of sialic acid-based molecules with potential therapeutic relevance. Molecular Insights into the Engagement of High-Affinity Sialylated Ligands to Human CD22.,Ereno-Orbea J, Pang L, Sicard T, Nycholat C, Cui H, Borovsky D, Franconetti A, Jimenez-Barbero J, Paulson JC, Julien JP JACS Au. 2025 Nov 5;5(11):5524-5537. doi: 10.1021/jacsau.5c01013. eCollection , 2025 Nov 24. PMID:41311955[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
