View source for 6fg2


==CRYSTAL STRUCTURE OF FAB OF NATALIZUMAB IN COMPLEX WITH FAB OF NAA84.==
<StructureSection load='6fg2' size='340' side='right'caption='[[6fg2]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6fg2]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FG2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FG2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.788&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6fg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fg2 OCA], [https://pdbe.org/6fg2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fg2 RCSB], [https://www.ebi.ac.uk/pdbsum/6fg2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fg2 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Natalizumab (NZM), a humanized monoclonal IgG4 antibody to alpha4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)(1,2), but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation(3,4). To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4(+) T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to alpha4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.

A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients.,Cassotta A, Mikol V, Bertrand T, Pouzieux S, Le Parc J, Ferrari P, Dumas J, Auer M, Deisenhammer F, Gastaldi M, Franciotta D, Silacci-Fregni C, Fernandez Rodriguez B, Giacchetto-Sasselli I, Foglierini M, Jarrossay D, Geiger R, Sallusto F, Lanzavecchia A, Piccoli L Nat Med. 2019 Sep;25(9):1402-1407. doi: 10.1038/s41591-019-0568-2. Epub 2019 Sep , 9. PMID:31501610<ref>PMID:31501610</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6fg2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bertrand T]]
[[Category: Pouzieux S]]