4oqt
LINGO-1/Li81 Fab complex
Structural highlights
DiseaseLIGO1_HUMAN Hereditary essential tremor. FunctionLIGO1_HUMAN Functional component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors. Is also an important negative regulator of oligodentrocyte differentiation and axonal myelination. Acts in conjunction with RTN4 and RTN4R in regulating neuronal precursor cell motility during cortical development (By similarity).[1] [2] [3] [4] Publication Abstract from PubMedMultiple sclerosis (MS) is an autoimmune-inflammatory induced disease of the central nervous system (CNS) with prominent demyelination and axonal injury. While most MS therapies target the immunological response, there is a large unmet need for treatments that can promote CNS repair. LINGO-1 (leucine-rich repeat and Ig containing Nogo receptor interacting protein-1) is a membrane protein selectively expressed in the CNS that suppresses myelination, preventing the repair of damaged axons. We are investigating LINGO-1 antagonist antibodies that lead to remyelination as a new paradigm for treatment of individuals with MS. The anti-LINGO-1 Li81 antibody (BIIB033) is currently in clinical trials and is the first MS treatment targeting CNS repair. Here, to elucidate the mechanism of action of the antibody, we solved the crystal structure of the LINGO-1/Li81 Fab complex and used biochemical and functional studies to investigate structure-function relationships. Li81 binds to the convex surface of the leucine-rich repeat domain of LINGO-1 within repeats 4-8. Fab binding blocks contact points used in the oligomerization of LINGO-1 and produces a stable complex containing 2 copies each of LINGO-1 and Fab that results from a rearrangement of contacts stabilizing the quaternary structure of LINGO-1. The formation of the LINGO-1/Li81 Fab complex masks functional epitopes within the Ig domain of LINGO-1 that are important for its biological activity in oligodendrocyte differentiation. These studies provide new insights into the structure and biology of LINGO-1 and how Li81 mAb can block its function. Structure of the LINGO-1-anti-LINGO-1 Li81 antibody complex provides insights into the biology of LINGO-1 and the mechanism of action of the antibody therapy.,Pepinsky RB, Arndt JW, Quan C, Gao Y, Quintero-Monzon O, Lee X, Mi S J Pharmacol Exp Ther. 2014 Apr 22. PMID:24756303[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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