View source for 8vrb


==Structure of a synthetic antibody in complex with a class I MHC presenting a hapten-peptide conjugate==
<StructureSection load='8vrb' size='340' side='right'caption='[[8vrb]], [[Resolution|resolution]] 3.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8vrb]] is a 5 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=8VRB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8VRB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.25&#8491;</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=8vrb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8vrb OCA], [https://pdbe.org/8vrb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8vrb RCSB], [https://www.ebi.ac.uk/pdbsum/8vrb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8vrb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A3G8GE10_HUMAN A0A3G8GE10_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The HapImmune(TM) platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib-peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the V(H) and V(L) domains, binds HLAs in an unconventional, angled way, with V(L) making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten-peptide conjugates and to adjust its conformation to different HLAs presenting hapten-peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten-peptide antigens, which will inform the development of next-generation therapeutic antibodies.

Molecular basis for antibody recognition of multiple drug-peptide/MHC complexes.,Maso L, Rajak E, Bang I, Koide A, Hattori T, Neel BG, Koide S Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2319029121. doi: , 10.1073/pnas.2319029121. Epub 2024 May 23. PMID:38781214<ref>PMID:38781214</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8vrb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bang I]]
[[Category: Koide S]]
[[Category: Maso L]]