6bvh: Difference between revisions
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==Trypsin complexed with a modified sunflower trypsin inhibitor, SFTI-TCTR(N12,N14)== | |||
<StructureSection load='6bvh' size='340' side='right'caption='[[6bvh]], [[Resolution|resolution]] 1.93Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6bvh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Helianthus_annuus Helianthus annuus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BVH 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]] 1.927Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6bvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bvh OCA], [https://pdbe.org/6bvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bvh RCSB], [https://www.ebi.ac.uk/pdbsum/6bvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bvh ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TRY1_BOVIN TRY1_BOVIN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Engagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design. | |||
Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif.,Chen X, Riley BT, de Veer SJ, Hoke DE, Van Haeften J, Leahy D, Swedberg JE, Brattsand M, Hartfield PJ, Buckle AM, Harris JM PLoS One. 2019 Jan 22;14(1):e0210842. doi: 10.1371/journal.pone.0210842., eCollection 2019. PMID:30668585<ref>PMID:30668585</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Chen | <div class="pdbe-citations 6bvh" style="background-color:#fffaf0;"></div> | ||
[[Category: Riley | |||
==See Also== | |||
*[[Trypsin 3D structures|Trypsin 3D structures]] | |||
*[[Trypsin inhibitor 3D structures|Trypsin inhibitor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Helianthus annuus]] | |||
[[Category: Large Structures]] | |||
[[Category: Chen X]] | |||
[[Category: Riley BT]] | |||
Latest revision as of 08:06, 21 November 2024
Trypsin complexed with a modified sunflower trypsin inhibitor, SFTI-TCTR(N12,N14)Trypsin complexed with a modified sunflower trypsin inhibitor, SFTI-TCTR(N12,N14)
Structural highlights
FunctionPublication Abstract from PubMedEngagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design. Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif.,Chen X, Riley BT, de Veer SJ, Hoke DE, Van Haeften J, Leahy D, Swedberg JE, Brattsand M, Hartfield PJ, Buckle AM, Harris JM PLoS One. 2019 Jan 22;14(1):e0210842. doi: 10.1371/journal.pone.0210842., eCollection 2019. PMID:30668585[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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