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Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis.

التفاصيل البيبلوغرافية
العنوان: Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis.
المؤلفون: Miles LA; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: lmiles@svi.edu.au., Hermans SJ; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia., Crespi GAN; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia., Gooi JH; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia., Doughty L; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia., Nero TL; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia., Markulić J; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia., Ebneth A; Janssen Research & Development, a Division of Janssen Pharmaceutica N.V, 2340 Beerse, Belgium., Wroblowski B; Janssen Research & Development, a Division of Janssen Pharmaceutica N.V, 2340 Beerse, Belgium., Oehlrich D; Janssen Research & Development, a Division of Janssen Pharmaceutica N.V, 2340 Beerse, Belgium., Trabanco AA; Neuroscience Medicinal Chemistry, Janssen Research & Development, 45007 Toledo, Spain., Rives ML; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, CA 92121, USA., Royaux I; Janssen Research & Development, a Division of Janssen Pharmaceutica N.V, 2340 Beerse, Belgium., Hancock NC; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia., Parker MW; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3056, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: mparker@svi.edu.au.
المصدر: IScience [iScience] 2019 Sep 27; Vol. 19, pp. 110-118. Date of Electronic Publication: 2019 Jul 19.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 101724038 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2589-0042 (Electronic) Linking ISSN: 25890042 NLM ISO Abbreviation: iScience Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Cambridge, MA] : Cell Press, [2018]-
مستخلص: 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.
(Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
References: Neuron. 2013 May 22;78(4):631-43. (PMID: 23623698)
J Biol Chem. 2003 Aug 15;278(33):31007-19. (PMID: 12773526)
Nat Commun. 2017 Oct 2;8(1):764. (PMID: 28970495)
Immunity. 2017 Sep 19;47(3):566-581.e9. (PMID: 28930663)
Neurobiol Aging. 2015 Feb;36(2):571-82. (PMID: 25448602)
J Neurosci. 2007 Aug 22;27(34):9201-19. (PMID: 17715356)
J Neurosci. 2010 Mar 3;30(9):3482-8. (PMID: 20203208)
J Biol Chem. 2006 Oct 27;281(43):32774-83. (PMID: 16895906)
Science. 2009 Mar 27;323(5922):1722-5. (PMID: 19264983)
Acta Crystallogr D Biol Crystallogr. 2004 Feb;60(Pt 2):401-3. (PMID: 14747738)
Immunity. 2017 Sep 19;47(3):398-400. (PMID: 28930654)
Nat Genet. 2011 May;43(5):436-41. (PMID: 21460841)
Mol Neurodegener. 2017 Jun 29;12(1):50. (PMID: 28662669)
Nat Genet. 2011 May;43(5):429-35. (PMID: 21460840)
Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):E4170-9. (PMID: 27357658)
Trends Biochem Sci. 2016 Jun;41(6):519-531. (PMID: 27085506)
Biochem J. 2006 Jul 15;397(2):271-8. (PMID: 16623661)
Hum Mol Genet. 2014 May 15;23(10):2729-36. (PMID: 24381305)
J Mol Biol. 2008 Jan 11;375(2):437-47. (PMID: 18022638)
Chem Sci. 2014 Jun 1;5(6):2398-2406. (PMID: 24921038)
Nat Neurosci. 2018 Oct;21(10):1359-1369. (PMID: 30258234)
Nat Genet. 2017 Sep;49(9):1373-1384. (PMID: 28714976)
Mol Neurodegener. 2017 May 26;12(1):43. (PMID: 28549481)
Neurol Genet. 2016 Jul 26;2(4):e90. (PMID: 27504496)
Nat Neurosci. 2018 Jul;21(7):941-951. (PMID: 29950669)
Blood. 2009 Apr 2;113(14):3333-6. (PMID: 19196661)
Nat Rev Immunol. 2014 Jul;14(7):463-77. (PMID: 24962261)
J Neurosci. 2013 Aug 14;33(33):13320-5. (PMID: 23946390)
Nat Neurosci. 2013 Jul;16(7):848-50. (PMID: 23708142)
فهرسة مساهمة: Keywords: Components of the Immune System; Molecular Neuroscience; Molecular Structure; Neuroscience; Protein Structure Aspects
تواريخ الأحداث: Date Created: 20190802 Latest Revision: 20200928
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6669322
DOI: 10.1016/j.isci.2019.07.023
PMID: 31369984
قاعدة البيانات: MEDLINE
الوصف
تدمد:2589-0042
DOI:10.1016/j.isci.2019.07.023