Structural and Dynamic Basis of TREM2--DAP12 Stabilization by Small-Molecule Agonist VG-3927

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is an important microglial receptor implicated in Alzheimers disease, but the structural basis of small-molecule TREM2 agonism remains poorly understood. In particular, the clinical-stage agonist VG-3927 has been reported to promote TREM2-DAP12 complex formation, suggesting a mechanism distinct from conventional recognition at the ectodomain surface. Here, we propose that VG-3927 binds within a membrane-embedded interfacial cavity formed by the transmembrane helices of TREM2, DAP12A, and DAP12B. Our simulations support a stable and reproducible cavity-bound pose that is maintained across independent trajectories and is anchored by a persistent hotspot network dominated by hydrophobic and van der Waals interactions. Rather than merely occupying a pre-existing pocket, VG-3927 reshapes the surrounding transmembrane assembly by reinforcing selected interhelical contacts, strengthening receptor-adaptor hydrogen-bond coupling, and biasing the three-helix bundle toward a more compact, more upright, and more conformationally focused state. Importantly, the ligand-bound ensemble remains within a subdomain of the apo conformational landscape, consistent with stabilization of a pre-existing but less populated signaling-relevant state. Together, these findings support a membrane-asscosiated mechanism in which VG-3927 acts as a transmembrane interfacial molecular glue, biasing the TREM2-DAP12 complex toward a more compact, ordered, and signaling-competent state. This finding can provide a structural framework for understanding small-molecule TREM2 agonism.