4OQT

LINGO-1/Li81 Fab complex

Summary for 4OQT

• Entry DOI: 10.2210/pdb4oqt/pdb
• Descriptor: Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1, Light Chain of Li81 Fab, kappa 3, Heavy Chain of Li81 Fab, VH3-23, ... (6 entities in total)
• Functional Keywords: leucine rich repeat, ig domain, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 105886.24

Authors

Pepinsky, R.B.,Arndt, J.W.,Quan, C.,Gao, Y.,Quintero-Monzon, O.,Lee, X.,Mi, S. (deposition date: 2014-02-10, release date: 2014-05-14, Last modification date: 2024-10-16)

Primary citation

Pepinsky, R.B.,Arndt, J.W.,Quan, C.,Gao, Y.,Quintero-Monzon, O.,Lee, X.,Mi, S.
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.
J.Pharmacol.Exp.Ther., 350:110-123, 2014

PubMed Abstract: Multiple sclerosis (MS) is an autoimmune-inflammatory disease of the central nervous system (CNS) with prominent demyelination and axonal injury. While most MS therapies target the immunologic 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 two 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 biologic activity in oligodendrocyte differentiation. These studies provide new insights into the structure and biology of LINGO-1 and how Li81 monoclonal antibody can block its function.

PubMed: 24756303
DOI: 10.1124/jpet.113.211771

Experimental method

X-RAY DIFFRACTION (3.23 Å)