View source for 7lmx


==A HIGHLY SPECIFIC INHIBITOR OF INTEGRIN ALPHA-V BETA-6 WITH A DISULFIDE==
<StructureSection load='7lmx' size='340' side='right'caption='[[7lmx]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7lmx]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LMX 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]] 1.8&#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=7lmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lmx OCA], [https://pdbe.org/7lmx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lmx RCSB], [https://www.ebi.ac.uk/pdbsum/7lmx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lmx ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
The RGD (Arg-Gly-Asp)-binding integrins alphavbeta6 and alphavbeta8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous alphavbeta6 and alphavbeta8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective alphavbeta6 and alphavbeta8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the alphavbeta6 and the alphavbeta8 integrins. In a lung fibrosis mouse model, the alphavbeta6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

De novo design of highly selective miniprotein inhibitors of integrins alphavbeta6 and alphavbeta8.,Roy A, Shi L, Chang A, Dong X, Fernandez A, Kraft JC, Li J, Le VQ, Winegar RV, Cherf GM, Slocum D, Poulson PD, Casper GE, Vallecillo-Zuniga ML, Valdoz JC, Miranda MC, Bai H, Kipnis Y, Olshefsky A, Priya T, Carter L, Ravichandran R, Chow CM, Johnson MR, Cheng S, Smith M, Overed-Sayer C, Finch DK, Lowe D, Bera AK, Matute-Bello G, Birkland TP, DiMaio F, Raghu G, Cochran JR, Stewart LJ, Campbell MG, Van Ry PM, Springer T, Baker D Nat Commun. 2023 Sep 13;14(1):5660. doi: 10.1038/s41467-023-41272-z. PMID:37704610<ref>PMID:37704610</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Baker D]]
[[Category: Bera AK]]
[[Category: Dong X]]
[[Category: Roy A]]
[[Category: Shi L]]
[[Category: Springer TA]]