4mpu: Difference between revisions
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==Human beta-tryptase co-crystal structure with (6S,8R)-N,N'-bis[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-8-hydroxy-6-(1-hydroxycyclobutyl)-5,7-dioxaspiro[3.4]octane-6,8-dicarboxamide== | |||
<StructureSection load='4mpu' size='340' side='right'caption='[[4mpu]], [[Resolution|resolution]] 1.65Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4mpu]] is a 2 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=4MPU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MPU 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]] 1.649Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=X2A:(6S,8R)-N,N-BIS[3-({4-[3-(AMINOMETHYL)PHENYL]PIPERIDIN-1-YL}CARBONYL)PHENYL]-8-HYDROXY-6-(1-HYDROXYCYCLOBUTYL)-5,7-DIOXASPIRO[3.4]OCTANE-6,8-DICARBOXAMIDE'>X2A</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=4mpu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mpu OCA], [https://pdbe.org/4mpu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mpu RCSB], [https://www.ebi.ac.uk/pdbsum/4mpu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mpu ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TRYB1_HUMAN TRYB1_HUMAN] Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Tryptase, a serine protease released from mast cells, is implicated in many allergic and inflammatory disorders. Human tryptase is a donut-shaped tetramer with the active sites facing inward forming a central pore. Bivalent ligands spanning two active sites potently inhibit this configuration, but these large compounds have poor drug-like properties. To overcome some of these challenges, we developed self-assembling molecules, called coferons, which deliver a larger compound in two parts. Using a pharmacophoric core and reversibly binding linkers to span two active sites, we have successfully produced three novel homodimeric tryptase inhibitors. Upon binding to tryptase, compounds reassembled into flexible homodimers, with significant improvements in IC(50) (0.19 +/- 0.08 muM) over controls (5.50 +/- 0.09 muM), and demonstrate good activity in mast cell lines. These studies provide validation for this innovative technology that is especially well-suited for the delivery of dimeric drugs to modulate intracellular macromolecular targets. | |||
Target-Directed Self-Assembly of Homodimeric Drugs Against beta-Tryptase.,Giardina SF, Werner DS, Pingle M, Foreman KW, Bergstrom DE, Arnold LD, Barany F ACS Med Chem Lett. 2018 Jul 5;9(8):827-831. doi: 10.1021/acsmedchemlett.8b00204. , eCollection 2018 Aug 9. PMID:30128075<ref>PMID:30128075</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 4mpu" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: White | ==See Also== | ||
*[[Tryptase|Tryptase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Stein AJ]] | |||
[[Category: Suto RK]] | |||
[[Category: White A]] | |||
Latest revision as of 06:16, 21 November 2024
Human beta-tryptase co-crystal structure with (6S,8R)-N,N'-bis[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-8-hydroxy-6-(1-hydroxycyclobutyl)-5,7-dioxaspiro[3.4]octane-6,8-dicarboxamideHuman beta-tryptase co-crystal structure with (6S,8R)-N,N'-bis[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-8-hydroxy-6-(1-hydroxycyclobutyl)-5,7-dioxaspiro[3.4]octane-6,8-dicarboxamide
Structural highlights
FunctionTRYB1_HUMAN Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type (By similarity). Publication Abstract from PubMedTryptase, a serine protease released from mast cells, is implicated in many allergic and inflammatory disorders. Human tryptase is a donut-shaped tetramer with the active sites facing inward forming a central pore. Bivalent ligands spanning two active sites potently inhibit this configuration, but these large compounds have poor drug-like properties. To overcome some of these challenges, we developed self-assembling molecules, called coferons, which deliver a larger compound in two parts. Using a pharmacophoric core and reversibly binding linkers to span two active sites, we have successfully produced three novel homodimeric tryptase inhibitors. Upon binding to tryptase, compounds reassembled into flexible homodimers, with significant improvements in IC(50) (0.19 +/- 0.08 muM) over controls (5.50 +/- 0.09 muM), and demonstrate good activity in mast cell lines. These studies provide validation for this innovative technology that is especially well-suited for the delivery of dimeric drugs to modulate intracellular macromolecular targets. Target-Directed Self-Assembly of Homodimeric Drugs Against beta-Tryptase.,Giardina SF, Werner DS, Pingle M, Foreman KW, Bergstrom DE, Arnold LD, Barany F ACS Med Chem Lett. 2018 Jul 5;9(8):827-831. doi: 10.1021/acsmedchemlett.8b00204. , eCollection 2018 Aug 9. PMID:30128075[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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