View source for 9gwt


==crystal structure of 23ME-00610 Fab in complex with human CD200R1==
<StructureSection load='9gwt' size='340' side='right'caption='[[9gwt]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9gwt]] is a 3 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=9GWT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GWT 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]] 2.89&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <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=9gwt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9gwt OCA], [https://pdbe.org/9gwt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9gwt RCSB], [https://www.ebi.ac.uk/pdbsum/9gwt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9gwt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MO2R1_HUMAN MO2R1_HUMAN] Inhibitory receptor for the CD200/OX2 cell surface glycoprotein. Limits inflammation by inhibiting the expression of pro-inflammatory molecules including TNF-alpha, interferons, and inducible nitric oxide synthase (iNOS) in response to selected stimuli. Also binds to HHV-8 K14 viral CD200 homolog with identical affinity and kinetics as the host CD200.<ref>PMID:12960329</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human CD200R1 (hCD200R1), an immune inhibitory receptor expressed predominantly on T cells and myeloid cells, was identified as a promising immuno-oncology target by the 23andMe database. Blockade of CD200R1-dependent signaling enhances T cell-mediated antitumor activity in vitro and in vivo. 23ME-00610 is a potential first-in-class, humanized IgG1 investigational antibody that binds hCD200R1 with high affinity. We have previously shown that 23ME-00610 inhibits the hCD200R1 immune checkpoint function. Herein, we dissect the molecular mechanism of 23ME-00610 blockade of hCD200R1 by solving the crystal structure of 23ME-00610 Fab in complex with hCD200R1 and performing mutational studies, which show 23ME-00610 blocks the interaction between hCD200 and hCD200R1 through steric hindrance. However, 23ME-00610 does not bind CD200R1 of preclinical species such as cynomolgus monkey MfCD200R1. To enable preclinical toxicology studies of CD200R1 blockade in a pharmacologically relevant non-clinical species, we engineered a surrogate antibody with high affinity toward MfCD200R1. We used phage display libraries of 23ME-00610 variants with individual CDR residues randomized to all 20 amino acids, from which we identified mutations that switched on MfCD200R1 binding. Structural analysis suggests how the surrogate, named 23ME-00611, acquires the ortholog binding ability at the equivalent epitope of 23ME-00610. This engineering approach does not require a priori knowledge of structural and functional mapping of antibody-antigen interaction and thus is generally applicable for therapeutic antibody development when desired ortholog binding is lacking. These findings provide foundational insights as 23ME-00610 advances in clinical studies to gain understanding of the hCD200R1 immune checkpoint as a target in immuno-oncology.

CD200R1 immune checkpoint blockade by the first-in-human anti-CD200R1 antibody 23ME-00610: molecular mechanism and engineering of a surrogate antibody.,Melero C, Budiardjo SJ, Daruwalla A, Larrabee L, Ganichkin O, Heiler AJ, Fenaux J, Chung B, Fuh G, Huang YM MAbs. 2024 Jan-Dec;16(1):2410316. doi: 10.1080/19420862.2024.2410316. Epub 2024 , Oct 14. PMID:39402718<ref>PMID:39402718</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9gwt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ganichkin OM]]
[[Category: Huang YM]]