Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes A beta Phagocytosis
Luke A Miles, Stefan J Hermans, Gabriela AN Crespi, Jonathan H Gooi, Larissa Doughty, Tracy L Nero, Jasmina Markulic, Andreas Ebneth, Berthold Wroblowski, Daniel Oehlrich, Andres A Trabanco, Marie-Laure Rives, Ines Royaux, Nancy C Hancock, Michael W Parker
ISCIENCE | CELL PRESS | Published : 2019
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. W..View full abstract
Awarded by Innovative Medicines Initiative 2 Joint Undertaking (IM12 JU)
This research was partly undertaken on the MX1 and MX2 beamlines at the Australian Synchrotron, ANSTO, Victoria, Australia, and we thank the beamline staff for their assistance. This work on the MX2 beamline made use of the ACRF detector. We thank Susanne Fell for help in early X-ray data collection. This work was supported by grants from the Bethlehem Griffiths Research Foundation, Mason Foundation, Yulgilbar Foundation, the Pratt Family, the Australian Cancer Research Foundation, and the Alzheimer's Drug Discovery Foundation to M.W.P. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (IM12 JU) under grant agreement No. 115976. Funding from the Victorian Government Operational Infrastructure Support Scheme to St. Vincent's Institute is acknowledged. J.M. is an Australian Rotary Health/Rotary District 9650 scholar and M.W.P. is a National Health and Medical Research Council of Australia Research Fellow. This research was supported in part by a research collaboration agreement established by Johnson & Johnson Innovation between St. Vincent's Institute and Janssen Pharmaceuticals.