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4c41

From Proteopedia

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Current revision

Corticosteroid-binding globulin with engineered disulphide bridge between residues 100 and 236

Structural highlights

4c41 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhou A, Wei Z, Stanley PL, Read RJ, Stein PE, Carrell RW. The S-to-R transition of corticosteroid-binding globulin and the mechanism of hormone release. J Mol Biol. 2008 Jun 27;380(1):244-51. Epub 2008 May 14. PMID:18513745 doi:10.1016/j.jmb.2008.05.012
↑ Chan WL, Zhou A, Read RJ. Towards engineering hormone-binding globulins as drug delivery agents. PLoS One. 2014 Nov 26;9(11):e113402. doi: 10.1371/journal.pone.0113402., eCollection 2014. PMID:25426859 doi:http://dx.doi.org/10.1371/journal.pone.0113402

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4c41"

Categories: Homo sapiens | Large Structures | Chan WL | Read RJ | Zhou A

@@ Line 3: / Line 3: @@
 <StructureSection load='4c41' size='340' side='right'caption='[[4c41]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4c41]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 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=4C41 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C41 FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c49|4c49]]</td></tr>
+</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'>[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://pdbe.org/4c41 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c41 RCSB], [http://www.ebi.ac.uk/pdbsum/4c41 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c41 ProSAT]</span></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=4c41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c41 OCA], [https://pdbe.org/4c41 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c41 RCSB], [https://www.ebi.ac.uk/pdbsum/4c41 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c41 ProSAT]</span></td></tr>
 </table>
 == 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.
+[https://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 ==
-[[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>
+[https://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 ==
@@ Line 27: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chan, W L]]
+[[Category: Chan WL]]
-[[Category: Read, R J]]
+[[Category: Read RJ]]
-[[Category: Zhou, A]]
+[[Category: Zhou A]]
-[[Category: Engineered disulphide]]
-[[Category: Serpin]]
-[[Category: Transport protein]]

4c41

From Proteopedia

Current revision

Corticosteroid-binding globulin with engineered disulphide bridge between residues 100 and 236

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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