Crystal structure of the β2-microglobulin-BBM.1 antibody complex reveals the molecular basis of antigen recognition.

Abstract

β2-Microglobulin (β2M) is an essential component of major histocompatibility complex class I (MHC-I) molecules, with a well established canonical role in immune surveillance. Beyond its classical functions, accumulating evidence has highlighted β2M as a multifaceted biomarker, with elevated serum levels closely associated with disease burden and prognosis in metabolic disorders, malignancies, autoimmune diseases and central nervous system conditions. In this study, we resolved the crystal structure of human β2M in complex with the mouse monoclonal antibody BBM.1 at 2.50 Å resolution using X-ray crystallography. Structural analysis revealed that BBM.1 binds β2M through multiple CDRs, recognizing key surface residues including Glu36, Asp38, Lys41, Asn42, Glu44, Arg45, Glu47 and Arg81. The interaction is anchored by a central hydrophobic core formed by Trp32 (light chain), Trp99 (heavy chain) and Ile92 (β2M), which is deeply buried in the interface. Surrounding this core is a well organized polar interaction network composed of hydrogen bonds and salt bridges, primarily involving β2M residues Lys41, Glu44, Arg45 and Glu47. Notably, the Arg45 residue deeply embeds into the antibody-binding pocket, forming several crucial interactions. These findings not only validate previous biochemical and mutational data but also identify new epitope residues, providing a structural foundation for the development and optimization of precision therapeutic strategies targeting β2M.