6d4a
Cell Surface Receptor with Bound Ligand at 1.75-A Resolution
Structural highlights
FunctionCD33_HUMAN Putative adhesion molecule of myelomonocytic-derived cells that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, may act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules. Induces apoptosis in acute myeloid leukemia (in vitro).[1] [2] Publication Abstract from PubMedPolymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer disease (AD), and reduced expression of the CD33 sialic acid-binding domain confers protection. Thus, CD33 inhibition might be an effective therapy against disease progression. Progress toward discovery of selective CD33 inhibitors has been hampered by the absence of an atomic resolution structure. We report here the crystal structures of CD33 alone and bound to a subtype-selective sialic acid mimetic called P22 and use them to identify key binding residues by site-directed mutagenesis and binding assays to reveal the molecular basis for its selectivity toward sialylated glycoproteins and glycolipids. We show that P22, when presented on microparticles, increases uptake of the toxic AD peptide, amyloid-beta (Abeta), into microglial cells. Thus, the sialic acid-binding site on CD33 is a promising pharmacophore for developing therapeutics that promote clearance of the Abeta peptide that is thought to cause AD. Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Abeta Phagocytosis.,Miles LA, Hermans SJ, Crespi GAN, Gooi JH, Doughty L, Nero TL, Markulic J, Ebneth A, Wroblowski B, Oehlrich D, Trabanco AA, Rives ML, Royaux I, Hancock NC, Parker MW iScience. 2019 Sep 27;19:110-118. doi: 10.1016/j.isci.2019.07.023. Epub 2019 Jul , 19. PMID:31369984[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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