PDBsum entry 4oqt

Membrane protein/immune system

PDB id: 4oqt

Contents

Protein chains

475 a.a.

214 a.a.

221 a.a.

Ligands

NAG-NAG-BMA ×3

NAG-NAG ×2

NAG ×2

PDB id:

4oqt

Name:

Membrane protein/immune system

Title:

Lingo-1/li81 fab complex

Structure:

Leucine-rich repeat and immunoglobulin-like domain- containing nogo receptor-interacting protein 1. Chain: a. Fragment: unp residues 40-517. Synonym: leucine-rich repeat and immunoglobulin domain-containing protein 1, leucine-rich repeat neuronal protein 1, leucine-rich repeat neuronal protein 6a. Engineered: yes. Light chain of li81 fab, kappa 3.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lingo1, lern1, lrrn6a, unq201/pro227. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_taxid: 10029

Resolution:

3.23Å R-factor: 0.195 R-free: 0.256

Authors:

R.B.Pepinsky,J.W.Arndt,C.Quan,Y.Gao,O.Quintero-Monzon,X.Lee,S.Mi

Key ref:

R.B.Pepinsky et al. (2014). 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. PubMed id: 24756303 DOI: 10.1124/jpet.113.211771

Date:

10-Feb-14 Release date: 14-May-14

Protein chain

Q96FE5  (LIGO1_HUMAN) -  Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 from Homo sapiens

Seq: 620 a.a.

Struc: 475 a.a.

Protein chain

Q6PIL8  (Q6PIL8_HUMAN) -  IGK@ protein from Homo sapiens

Seq: 236 a.a.

Struc: 214 a.a.*

Protein chain

S6B291  (S6B291_HUMAN) -  IgG H chain from Homo sapiens

Seq: 466 a.a.

Struc: 221 a.a.*

* PDB and UniProt seqs differ at 39 residue positions (black crosses)

DOI no: 10.1124/jpet.113.211771

J Pharmacol Exp Ther 350:110-123 (2014)

PubMed id: 24756303

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.

R.B.Pepinsky, J.W.Arndt, C.Quan, Y.Gao, O.Quintero-Monzon, X.Lee, S.Mi.

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.