6D49

Cell Surface Receptor in Complex with Ligand at 1.80-A Resolution

Summary for 6D49

• Entry DOI: 10.2210/pdb6d49/pdb
• Related: 6D48 6D4A
• Descriptor: Myeloid cell surface antigen CD33, GLYCEROL, 2-aminoethyl 5-{[(4-cyclohexyl-1H-1,2,3-triazol-1-yl)acetyl]amino}-3,5,9-trideoxy-9-[(4-hydroxy-3,5-dimethylbenzene-1-carbonyl)amino]-D-glycero-alpha-D-galacto-non-2-ulopyranonosyl-(2->6)-beta-D-galactopyranosyl-(1->4)-beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: sialic acid binding, transmembrane, receptor, siglec, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 32071.41

Authors

Hermans, S.J.,Miles, L.A.,Parker, M.W. (deposition date: 2018-04-17, release date: 2019-04-17, Last modification date: 2024-10-30)

Primary citation

Miles, L.A.,Hermans, S.J.,Crespi, G.A.N.,Gooi, J.H.,Doughty, L.,Nero, T.L.,Markulic, J.,Ebneth, A.,Wroblowski, B.,Oehlrich, D.,Trabanco, A.A.,Rives, M.L.,Royaux, I.,Hancock, N.C.,Parker, M.W.
Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes A beta Phagocytosis.
Iscience, 19:110-118, 2019

PubMed Abstract: Polymorphism 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-β (Aβ), into microglial cells. Thus, the sialic acid-binding site on CD33 is a promising pharmacophore for developing therapeutics that promote clearance of the Aβ peptide that is thought to cause AD.

PubMed: 31369984
DOI: 10.1016/j.isci.2019.07.023

Experimental method

X-RAY DIFFRACTION (1.801 Å)