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PDBsum entry 4oqt
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Membrane protein/immune system
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PDB id
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4oqt
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Contents |
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475 a.a.
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214 a.a.
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221 a.a.
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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R.B.Pepinsky,
J.W.Arndt,
C.Quan,
Y.Gao,
O.Quintero-Monzon,
X.Lee,
S.Mi.
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Ref.
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J Pharmacol Exp Ther, 2014,
350,
110-123.
[DOI no: ]
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PubMed id
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Abstract
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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.
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