6y6c: Difference between revisions
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==== | ==TREM2 extracellular domain (19-174) in complex with single-chain variable fragment (scFv-4)== | ||
<StructureSection load='6y6c' size='340' side='right'caption='[[6y6c]]' scene=''> | <StructureSection load='6y6c' size='340' side='right'caption='[[6y6c]], [[Resolution|resolution]] 2.26Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[6y6c]] is a 4 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=6Y6C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Y6C FirstGlance]. <br> | ||
</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=6y6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y6c OCA], [https://pdbe.org/6y6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6y6c RCSB], [https://www.ebi.ac.uk/pdbsum/6y6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6y6c ProSAT]</span></td></tr> | </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=6y6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y6c OCA], [https://pdbe.org/6y6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6y6c RCSB], [https://www.ebi.ac.uk/pdbsum/6y6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6y6c ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/TREM2_HUMAN TREM2_HUMAN] Progressive non-fluent aphasia;Amyotrophic lateral sclerosis;Nasu-Hakola disease;Semantic dementia;Behavioral variant of frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TREM2_HUMAN TREM2_HUMAN] May have a role in chronic inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines. Forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells.<ref>PMID:10799849</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration, including Alzheimer's disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signaling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterized. Here, we present phage display generated antibody single-chain variable fragments (scFvs) to human TREM2 immunoglobulin-like domain. Co-crystal structures revealed the binding of two scFvs to an epitope on the TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species, which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterization of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research. | |||
Selection and structural characterization of anti-TREM2 scFvs that reduce levels of shed ectodomain.,Szykowska A, Chen Y, Smith TB, Preger C, Yang J, Qian D, Mukhopadhyay SM, Wigren E, Neame SJ, Graslund S, Persson H, Atkinson PJ, Di Daniel E, Mead E, Wang J, Davis JB, Burgess-Brown NA, Bullock AN Structure. 2021 Nov 4;29(11):1241-1252.e5. doi: 10.1016/j.str.2021.06.010. Epub , 2021 Jul 6. PMID:34233201<ref>PMID:34233201</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6y6c" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: Bountra C]] | |||
[[Category: Bullock A]] | |||
[[Category: Burgess-Brown N]] | |||
[[Category: Davis JB]] | |||
[[Category: Di Daniel E]] | |||
[[Category: Edwards A]] | |||
[[Category: Gruslund S]] | |||
[[Category: McKinley G]] | |||
[[Category: Mukhopadhyay SMM]] | |||
[[Category: Persson H]] | |||
[[Category: Preger C]] | |||
[[Category: Szykowska A]] | |||
[[Category: Wigren E]] | |||
[[Category: Williams E]] | |||
[[Category: Von Delft F]] | |||
Revision as of 13:04, 21 December 2022
TREM2 extracellular domain (19-174) in complex with single-chain variable fragment (scFv-4)TREM2 extracellular domain (19-174) in complex with single-chain variable fragment (scFv-4)
Structural highlights
DiseaseTREM2_HUMAN Progressive non-fluent aphasia;Amyotrophic lateral sclerosis;Nasu-Hakola disease;Semantic dementia;Behavioral variant of frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry. FunctionTREM2_HUMAN May have a role in chronic inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines. Forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells.[1] Publication Abstract from PubMedMutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration, including Alzheimer's disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signaling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterized. Here, we present phage display generated antibody single-chain variable fragments (scFvs) to human TREM2 immunoglobulin-like domain. Co-crystal structures revealed the binding of two scFvs to an epitope on the TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species, which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterization of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research. Selection and structural characterization of anti-TREM2 scFvs that reduce levels of shed ectodomain.,Szykowska A, Chen Y, Smith TB, Preger C, Yang J, Qian D, Mukhopadhyay SM, Wigren E, Neame SJ, Graslund S, Persson H, Atkinson PJ, Di Daniel E, Mead E, Wang J, Davis JB, Burgess-Brown NA, Bullock AN Structure. 2021 Nov 4;29(11):1241-1252.e5. doi: 10.1016/j.str.2021.06.010. Epub , 2021 Jul 6. PMID:34233201[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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