6D49

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

6D49 の概要

• エントリーDOI: 10.2210/pdb6d49/pdb
• 関連するPDBエントリー: 6D48 6D4A
• 分子名称: 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)
• 機能のキーワード: sialic acid binding, transmembrane, receptor, siglec, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32071.41

構造登録者

Hermans, S.J.,Miles, L.A.,Parker, M.W. (登録日: 2018-04-17, 公開日: 2019-04-17, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.801 Å)