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| | <StructureSection load='6d4a' size='340' side='right'caption='[[6d4a]], [[Resolution|resolution]] 1.75Å' scene=''> | | <StructureSection load='6d4a' size='340' side='right'caption='[[6d4a]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6d4a]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D4A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D4A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6d4a]] is a 2 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=6D4A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D4A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FVP: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'>FVP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.751Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6d48|6d48]], [[6d49|6d49]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FVP: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'>FVP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CD33, SIGLEC3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6d4a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4a OCA], [https://pdbe.org/6d4a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d4a RCSB], [https://www.ebi.ac.uk/pdbsum/6d4a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4a ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6d4a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4a OCA], [http://pdbe.org/6d4a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d4a RCSB], [http://www.ebi.ac.uk/pdbsum/6d4a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4a ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CD33_HUMAN CD33_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).<ref>PMID:10556798</ref> <ref>PMID:11320212</ref> | + | [https://www.uniprot.org/uniprot/CD33_HUMAN CD33_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).<ref>PMID:10556798</ref> <ref>PMID:11320212</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Hermans, S J]] | + | [[Category: Hermans SJ]] |
| - | [[Category: Miles, L A]] | + | [[Category: Miles LA]] |
| - | [[Category: Parker, M W]] | + | [[Category: Parker MW]] |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Sialic acid binding]]
| + | |
| - | [[Category: Siglec]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| Structural highlights
Function
CD33_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 PubMed
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-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
- ↑ Ulyanova T, Blasioli J, Woodford-Thomas TA, Thomas ML. The sialoadhesin CD33 is a myeloid-specific inhibitory receptor. Eur J Immunol. 1999 Nov;29(11):3440-9. PMID:10556798 doi:http://dx.doi.org/10.1002/(SICI)1521-4141(199911)29:11<3440::AID-IMMU3440>3.0.CO;2-C
- ↑ Vitale C, Romagnani C, Puccetti A, Olive D, Costello R, Chiossone L, Pitto A, Bacigalupo A, Moretta L, Mingari MC. Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: engagement of CD33 induces apoptosis of leukemic cells. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5764-9. Epub 2001 Apr 24. PMID:11320212 doi:http://dx.doi.org/10.1073/pnas.091097198
- ↑ 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. Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Abeta Phagocytosis. iScience. 2019 Sep 27;19:110-118. doi: 10.1016/j.isci.2019.07.023. Epub 2019 Jul , 19. PMID:31369984 doi:http://dx.doi.org/10.1016/j.isci.2019.07.023
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