Abstract
Chemokine-like receptor CCRL2 is a nonsignaling atypical GPCR that presents chemerin to its cognate receptor CMKLR1 (ChemerinR1), a process essential for the recruitment of inflammatory cells. Despite their biological importance, the structural determinants of CCRL2-chemerin recognition remain poorly defined. Here, we present a comprehensive multiscale computational study that integrates coarse-grained and all-atom molecular dynamics simulations with structural modeling to investigate CCRL2-chemerin interaction. Our results reveal a flexible yet stable binding interface primarily mediated by chemerin's β1 strand and CCRL2's extracellular loop 2, while the C-terminal region of chemerin remains accessible for CMKLR1 engagement. Electrostatic interactions between CCRL2 N-terminus and chemerin's loop 3 further stabilize the complex without triggering intracellular signaling. A modeled ternary CCRL2-chemerin-CMKLR1 complex provides a putative mechanistic framework in which CCRL2 aligns chemerin to promote efficient CMKLR1 activation. Mapping of naturally occurring missense variants onto this interface suggests that sequence variation at specific residues may influence receptor-ligand stability and function. Together, these findings suggest a structural basis of CCRL2-mediated chemerin presentation and may help improve our understanding of its role in immune signaling.