6xds

Publication Abstract from PubMed

TREM2 has been identified by genomic analysis as a potential and novel target for the treatment of Alzheimer's disease. To enable structure-based screening of potential small molecule therapeutics, we sought to develop a robust crystallization platform for the TREM2 Ig-like domain. A systematic set of constructs containing the structural chaperone, maltose binding protein (MBP), fused to the Ig domain of TREM2, were evaluated in parallel expression and purification, followed by crystallization studies. Using protein crystallization and high-resolution diffraction as a readout, a MBP-TREM2 Ig fusion construct was identified that generates reproducible protein crystals diffracting at 2.0 A, which makes it suitable for soaking of potential ligands. Importantly, analysis of crystal packing interfaces indicates that most of the surface of the TREM2 Ig domain is available for small molecule binding. A proof of concept co-crystallization study with a small library of fragments validated potential utility of this system for the discovery of new TREM2 therapeutics.

Development of a robust crystallization platform for immune receptor TREM2 using a crystallization chaperone strategy.,Byrne NJ, Lee AC, Kostas J, Reid JC, Partridge AT, So SS, Cowan JE, Abeywickrema P, Huang H, Zebisch M, Barker JJ, Soisson SM, Brooun A, Su HP Protein Expr Purif. 2021 Mar;179:105796. doi: 10.1016/j.pep.2020.105796. Epub, 2020 Nov 20. PMID:33221505^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.