5om6: Difference between revisions
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==Crystal structure of Alpha1-antichymotrypsin variant DBS-I-allo2: a MMP9-cleavable drug-binding serpin for doxycycline== | |||
<StructureSection load='5om6' size='340' side='right' caption='[[5om6]], [[Resolution|resolution]] 1.85Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5om6]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OM6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OM6 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5om6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5om6 OCA], [http://pdbe.org/5om6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5om6 RCSB], [http://www.ebi.ac.uk/pdbsum/5om6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5om6 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/AACT_HUMAN AACT_HUMAN]] Although its physiological function is unclear, it can inhibit neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2.<ref>PMID:2404007</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The allosteric interplay between distant functional sites present in a single protein provides for one of the most important regulatory mechanisms in biological systems. While the design of ligand-binding sites into proteins remains challenging, this holds even truer for the coupling of a newly engineered binding site to an allosteric mechanism that regulates the ligand affinity. Here it is shown how computational design algorithms enabled the introduction of doxycycline- and doxorubicin-binding sites into the serine proteinase inhibitor (serpin) family member alpha1-antichymotrypsin. Further engineering allowed exploitation of the proteinase-triggered serpin-typical S-to-R transition to modulate the ligand affinities. These design variants follow strategies observed in naturally occurring plasma globulins that allow for the targeted delivery of hormones in the blood. By analogy, we propose that the variants described in the present study could be further developed to allow for the delivery of the antibiotic doxycycline and the anticancer compound doxorubicin to tissues/locations that express specific proteinases, such as bacterial infection sites or tumor cells secreting matrix metalloproteinases. | |||
Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein.,Schmidt K, Gardill BR, Kern A, Kirchweger P, Borsch M, Muller YA Proc Natl Acad Sci U S A. 2018 May 14. pii: 1716666115. doi:, 10.1073/pnas.1716666115. PMID:29760101<ref>PMID:29760101</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5om6" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Muller, Y A]] | |||
[[Category: Schmidt, K]] | |||
[[Category: Alpha1-antichymotrypsin]] | |||
[[Category: Doxycycline-binding protein]] | |||
[[Category: Mmp9-cleavable rcl]] | |||
[[Category: Serpin]] | |||
[[Category: Transport protein]] | |||
Revision as of 10:13, 23 May 2018
Crystal structure of Alpha1-antichymotrypsin variant DBS-I-allo2: a MMP9-cleavable drug-binding serpin for doxycyclineCrystal structure of Alpha1-antichymotrypsin variant DBS-I-allo2: a MMP9-cleavable drug-binding serpin for doxycycline
Structural highlights
Function[AACT_HUMAN] Although its physiological function is unclear, it can inhibit neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2.[1] Publication Abstract from PubMedThe allosteric interplay between distant functional sites present in a single protein provides for one of the most important regulatory mechanisms in biological systems. While the design of ligand-binding sites into proteins remains challenging, this holds even truer for the coupling of a newly engineered binding site to an allosteric mechanism that regulates the ligand affinity. Here it is shown how computational design algorithms enabled the introduction of doxycycline- and doxorubicin-binding sites into the serine proteinase inhibitor (serpin) family member alpha1-antichymotrypsin. Further engineering allowed exploitation of the proteinase-triggered serpin-typical S-to-R transition to modulate the ligand affinities. These design variants follow strategies observed in naturally occurring plasma globulins that allow for the targeted delivery of hormones in the blood. By analogy, we propose that the variants described in the present study could be further developed to allow for the delivery of the antibiotic doxycycline and the anticancer compound doxorubicin to tissues/locations that express specific proteinases, such as bacterial infection sites or tumor cells secreting matrix metalloproteinases. Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein.,Schmidt K, Gardill BR, Kern A, Kirchweger P, Borsch M, Muller YA Proc Natl Acad Sci U S A. 2018 May 14. pii: 1716666115. doi:, 10.1073/pnas.1716666115. PMID:29760101[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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