4oqt

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(Difference between revisions)

Revision as of 05:30, 18 June 2014

LINGO-1/Li81 Fab complex

Structural highlights

4oqt is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[LIGO1_HUMAN] Hereditary essential tremor.

Function

[LIGO1_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 PubMed

Multiple 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

↑ Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci. 2004 Mar;7(3):221-8. Epub 2004 Feb 15. PMID:14966521 doi:http://dx.doi.org/10.1038/nn1188
↑ Mi S, Miller RH, Lee X, Scott ML, Shulag-Morskaya S, Shao Z, Chang J, Thill G, Levesque M, Zhang M, Hession C, Sah D, Trapp B, He Z, Jung V, McCoy JM, Pepinsky RB. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005 Jun;8(6):745-51. Epub 2005 May 15. PMID:15895088 doi:http://dx.doi.org/nn1460
↑ Park JB, Yiu G, Kaneko S, Wang J, Chang J, He XL, Garcia KC, He Z. A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron. 2005 Feb 3;45(3):345-51. PMID:15694321 doi:http://dx.doi.org/10.1016/j.neuron.2004.12.040
↑ Mosyak L, Wood A, Dwyer B, Buddha M, Johnson M, Aulabaugh A, Zhong X, Presman E, Benard S, Kelleher K, Wilhelm J, Stahl ML, Kriz R, Gao Y, Cao Z, Ling HP, Pangalos MN, Walsh FS, Somers WS. The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. J Biol Chem. 2006 Nov 24;281(47):36378-90. Epub 2006 Sep 27. PMID:17005555 doi:M607314200
↑ Pepinsky RB, Arndt JW, 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. 2014 Apr 22. PMID:24756303 doi:http://dx.doi.org/10.1124/jpet.113.211771

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4oqt"

@@ Line 2: / Line 2: @@
 <StructureSection load='4oqt' size='340' side='right' caption='[[4oqt]], [[Resolution|resolution]] 3.23&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4oqt]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OQT OCA]. <br>
+<table><tr><td colspan='2'>[[4oqt]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OQT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OQT FirstGlance]. <br>
 </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene><br>
-<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>
 <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4oqt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oqt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4oqt RCSB], [http://www.ebi.ac.uk/pdbsum/4oqt PDBsum]</span></td></tr>
 <table>
@@ Line 17: / Line 16: @@
 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<ref>PMID:24756303</ref>
-From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 == References ==

4oqt

From Proteopedia

Revision as of 05:30, 18 June 2014

LINGO-1/Li81 Fab complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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