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Structural modeling and biochemical studies reveal insights into the molecular basis of the recognition of β ‐2‐microglobulin by antibody BBM.1
Author(s) -
Du Jiamu,
Yang Hui,
Peng Baozhen,
Ding Jianping
Publication year - 2009
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.964
Subject(s) - beta 2 microglobulin , basis (linear algebra) , antibody , chemistry , computational biology , biology , mathematics , immunology , geometry
Abstract Human β ‐2‐microglobulin ( β 2m) is the light chain of human leucocyte antigen‐I (HLA‐I). It can disassociate from HLA‐I and accumulate to cause serious dialysis‐related amyloidosis (DRA) in long‐term hemodialysis patients. Monoclonal antibody (mAb) BBM.1 can recognize both free‐form and HLA‐I associated β 2m. It can be used for specific elimination of β 2m from serum and can induce apoptosis of several types of tumor cells, and thus has great therapeutic potential. In this study, we constructed structural models of the BBM.1 Fv (fragment of the variable domain) and the BBM.1 Fv‐ β 2m complex, followed by biochemical evaluation. Analysis of the optimal complex model reveals that the previously identified immunodominant residues Glu 44 and Arg 45 of β 2m have direct interactions with BBM.1, while Asp 38 exerts its function mainly via stabilization of Arg 45 . In addition, Arg 81 of β 2m is a newly identified immunodominant residue to have direct interaction with BBM.1. Further modeling study shows no steric conflict between the antibody and the HLA‐I heavy chain. These results provide insights into the molecular basis of the recognition of β 2m by BBM.1 and explain why BBM.1 can bind both free‐form and HLA‐1 associated β 2m. This information could be exploited in the engineering and improvement of BBM.1 and the development of other β 2m‐targeting mAbs for therapeutic purposes. Copyright © 2009 John Wiley & Sons, Ltd.