View source for 8ttm


==IgG1 Fc Heterodimer combYSelect1==
<StructureSection load='8ttm' size='340' side='right'caption='[[8ttm]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ttm]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens_x_Mus_musculus_hybrid_cell_line Homo sapiens x Mus musculus hybrid cell line]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8TTM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TTM 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]] 2.51&#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=FUC:ALPHA-L-FUCOSE'>FUC</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=8ttm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ttm OCA], [https://pdbe.org/8ttm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ttm RCSB], [https://www.ebi.ac.uk/pdbsum/8ttm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ttm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IGG1_HUMAN IGG1_HUMAN] Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).<ref>PMID:17576170</ref> <ref>PMID:20176268</ref> <ref>PMID:22158414</ref> 
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== Publication Abstract from PubMed ==
Redesigning protein-protein interfaces is an important tool for developing therapeutic strategies. Interfaces can be redesigned by in silico screening, which allows for efficient sampling of a large protein space before experimental validation. However, computational costs limit the number of combinations that can be reasonably sampled. Here, we present combinatorial tyrosine (Y)/serine (S) selection (combYSelect), a computational approach combining in silico determination of the change in binding free energy (DeltaDeltaG) of an interface with a highly restricted library composed of just two amino acids, tyrosine and serine. We used combYSelect to design two immunoglobulin G (IgG) heterodimers-combYSelect1 (L368S/D399Y-K409S/T411Y) and combYSelect2 (D399Y/K447S-K409S/T411Y)-that exhibit near-optimal heterodimerization, without affecting IgG stability or function. We solved the crystal structures of these heterodimers and found that dynamic pi-stacking interactions and polar contacts drive preferential heterodimeric interactions. Finally, we demonstrated the utility of our combYSelect heterodimers by engineering both a bispecific antibody and a cytokine trap for two unique therapeutic applications.

Combinatorially restricted computational design of protein-protein interfaces to produce IgG heterodimers.,Azzam T, Du JJ, Flowers MW, Ali AV, Hunn JC, Vijayvargiya N, Knagaram R, Bogacz M, Maravillas KE, Sastre DE, Fields JK, Mirzaei A, Pierce BG, Sundberg EJ Sci Adv. 2024 Apr 12;10(15):eadk8157. doi: 10.1126/sciadv.adk8157. Epub 2024 Apr , 10. PMID:38598628<ref>PMID:38598628</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8ttm" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens x Mus musculus hybrid cell line]]
[[Category: Large Structures]]
[[Category: Azzam T]]
[[Category: Du JJ]]
[[Category: Sundberg EJ]]