7sjn: Difference between revisions

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'''Unreleased structure'''


The entry 7sjn is ON HOLD  until sometime in the future
==HtrA1:Fab15H6.v4 complex==
<StructureSection load='7sjn' size='340' side='right'caption='[[7sjn]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7sjn]] is a 9 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=7SJN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SJN 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]] 3.4&#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=7sjn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sjn OCA], [https://pdbe.org/7sjn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sjn RCSB], [https://www.ebi.ac.uk/pdbsum/7sjn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sjn ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 A away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases.


Authors:  
Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration.,Gerhardy S, Ultsch M, Tang W, Green E, Holden JK, Li W, Estevez A, Arthur C, Tom I, Rohou A, Kirchhofer D Nat Commun. 2022 Sep 5;13(1):5222. doi: 10.1038/s41467-022-32760-9. PMID:36064790<ref>PMID:36064790</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 7sjn" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Antibody 3D structures|Antibody 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arthur CP]]
[[Category: Estevez A]]
[[Category: Gerhardy S]]
[[Category: Green E]]
[[Category: Kirchhofer D]]
[[Category: Rohou A]]
[[Category: Ultsch M]]
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