4c41: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4c41]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C41 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C41 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4c41]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C41 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C41 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c49|4c49]]</td></tr> | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c49|4c49]]</td></tr> | ||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c41 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c41 RCSB], [http://www.ebi.ac.uk/pdbsum/4c41 PDBsum]</span></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=4c41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c41 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c41 RCSB], [http://www.ebi.ac.uk/pdbsum/4c41 PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Disease == | == Disease == | ||
[[http://www.uniprot.org/uniprot/CBG_HUMAN CBG_HUMAN]] Corticosteroid-binding globulin deficiency. The disease is caused by mutations affecting the gene represented in this entry. | [[http://www.uniprot.org/uniprot/CBG_HUMAN CBG_HUMAN]] Corticosteroid-binding globulin deficiency. The disease is caused by mutations affecting the gene represented in this entry. | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/CBG_HUMAN CBG_HUMAN]] Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.<ref>PMID:18513745</ref> | [[http://www.uniprot.org/uniprot/CBG_HUMAN CBG_HUMAN]] Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.<ref>PMID:18513745</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The treatment of many diseases such as cancer requires the use of drugs that can cause severe side effects. Off-target toxicity can often be reduced simply by directing the drugs specifically to sites of diseases. Amidst increasingly sophisticated methods of targeted drug delivery, we observed that Nature has already evolved elegant means of sending biological molecules to where they are needed. One such example is corticosteroid binding globulin (CBG), the major carrier of the anti-inflammatory hormone, cortisol. Targeted release of cortisol is triggered by cleavage of CBG's reactive centre loop by elastase, a protease released by neutrophils in inflamed tissues. This work aimed to establish the feasibility of exploiting this mechanism to carry therapeutic agents to defined locations. The reactive centre loop of CBG was altered with site-directed mutagenesis to favour cleavage by other proteases, to alter the sites at which it would release its cargo. Mutagenesis succeeded in making CBG a substrate for either prostate specific antigen (PSA), a prostate-specific serine protease, or thrombin, a key protease in the blood coagulation cascade. PSA is conspicuously overproduced in prostatic hyperplasia and is, therefore, a good way of targeting hyperplastic prostate tissues. Thrombin is released during clotting and consequently is ideal for conferring specificity to thrombotic sites. Using fluorescence-based titration assays, we also showed that CBG can be engineered to bind a new compound, thyroxine-6-carboxyfluorescein, instead of its physiological ligand, cortisol, thereby demonstrating that it is possible to tailor the hormone binding site to deliver a therapeutic drug. In addition, we proved that the efficiency with which CBG releases bound ligand can be increased by introducing some well-placed mutations. This proof-of-concept study has raised the prospect of a novel means of targeted drug delivery, using the serpin conformational change to combat the problem of off-target effects in the treatment of diseases. | |||
Towards engineering hormone-binding globulins as drug delivery agents.,Chan WL, Zhou A, Read RJ PLoS One. 2014 Nov 26;9(11):e113402. doi: 10.1371/journal.pone.0113402., eCollection 2014. PMID:25426859<ref>PMID:25426859</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Chan, W L | [[Category: Chan, W L]] | ||
[[Category: Read, R J | [[Category: Read, R J]] | ||
[[Category: Zhou, A | [[Category: Zhou, A]] | ||
[[Category: Engineered disulphide]] | [[Category: Engineered disulphide]] | ||
[[Category: Serpin]] | [[Category: Serpin]] | ||
[[Category: Transport protein]] | [[Category: Transport protein]] | ||
Revision as of 15:08, 10 December 2014
Corticosteroid-binding globulin with engineered disulphide bridge between residues 100 and 236Corticosteroid-binding globulin with engineered disulphide bridge between residues 100 and 236
Structural highlights
Disease[CBG_HUMAN] Corticosteroid-binding globulin deficiency. The disease is caused by mutations affecting the gene represented in this entry. Function[CBG_HUMAN] Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.[1] Publication Abstract from PubMedThe treatment of many diseases such as cancer requires the use of drugs that can cause severe side effects. Off-target toxicity can often be reduced simply by directing the drugs specifically to sites of diseases. Amidst increasingly sophisticated methods of targeted drug delivery, we observed that Nature has already evolved elegant means of sending biological molecules to where they are needed. One such example is corticosteroid binding globulin (CBG), the major carrier of the anti-inflammatory hormone, cortisol. Targeted release of cortisol is triggered by cleavage of CBG's reactive centre loop by elastase, a protease released by neutrophils in inflamed tissues. This work aimed to establish the feasibility of exploiting this mechanism to carry therapeutic agents to defined locations. The reactive centre loop of CBG was altered with site-directed mutagenesis to favour cleavage by other proteases, to alter the sites at which it would release its cargo. Mutagenesis succeeded in making CBG a substrate for either prostate specific antigen (PSA), a prostate-specific serine protease, or thrombin, a key protease in the blood coagulation cascade. PSA is conspicuously overproduced in prostatic hyperplasia and is, therefore, a good way of targeting hyperplastic prostate tissues. Thrombin is released during clotting and consequently is ideal for conferring specificity to thrombotic sites. Using fluorescence-based titration assays, we also showed that CBG can be engineered to bind a new compound, thyroxine-6-carboxyfluorescein, instead of its physiological ligand, cortisol, thereby demonstrating that it is possible to tailor the hormone binding site to deliver a therapeutic drug. In addition, we proved that the efficiency with which CBG releases bound ligand can be increased by introducing some well-placed mutations. This proof-of-concept study has raised the prospect of a novel means of targeted drug delivery, using the serpin conformational change to combat the problem of off-target effects in the treatment of diseases. Towards engineering hormone-binding globulins as drug delivery agents.,Chan WL, Zhou A, Read RJ PLoS One. 2014 Nov 26;9(11):e113402. doi: 10.1371/journal.pone.0113402., eCollection 2014. PMID:25426859[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||