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Development of a robust crystallization platform for immune receptor TREM2 using a crystallization chaperone strategy
Noel J Byrne1, Amy C Lee1, James Kostas1
1Department of Computational and Structural Sciences, Merck & Co., Inc., West Point, PA, USA.
Protein Expression and Purification
|November 22, 2020
Summary
Researchers developed a new method to crystallize the TREM2 Ig-like domain, a key target for Alzheimer's disease therapeutics. This breakthrough enables structure-based drug screening for novel Alzheimer's treatments.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Genomic analysis identified TREM2 (Triggering Receptor Expressed on Myeloid cells 2) as a novel therapeutic target for Alzheimer's disease.
- Structure-based drug discovery requires high-resolution structural information of the target protein.
Purpose of the Study:
- To develop a robust crystallization platform for the TREM2 Ig-like domain.
- To enable structure-based screening of small molecule therapeutics for Alzheimer's disease.
Main Methods:
- Systematic evaluation of maltose binding protein (MBP)-TREM2 Ig fusion constructs for expression and purification.
- Protein crystallization screening and high-resolution X-ray diffraction analysis.
- Proof-of-concept co-crystallization with small molecule fragments.
Main Results:
- An optimal MBP-TREM2 Ig fusion construct was identified, yielding reproducible protein crystals diffracting at 2.0 Å resolution.
- Analysis of crystal packing revealed significant surface accessibility of the TREM2 Ig domain for small molecule binding.
- Co-crystallization studies demonstrated the system's utility for identifying potential TREM2-binding ligands.
Conclusions:
- A high-resolution crystal structure of the TREM2 Ig-like domain has been obtained, suitable for structure-based drug discovery.
- This platform facilitates the identification of novel small molecule therapeutics targeting TREM2 for Alzheimer's disease treatment.
