1b0q
From Proteopedia
(New page: 200px<br /><applet load="1b0q" size="450" color="white" frame="true" align="right" spinBox="true" caption="1b0q" /> '''DITHIOL ALPHA MELANOTROPIN PEPTIDE CYCLIZED ...) |
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| - | [[Image:1b0q.gif|left|200px]]<br /><applet load="1b0q" size=" | + | [[Image:1b0q.gif|left|200px]]<br /><applet load="1b0q" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1b0q" /> | caption="1b0q" /> | ||
'''DITHIOL ALPHA MELANOTROPIN PEPTIDE CYCLIZED VIA RHENIUM METAL COORDINATION'''<br /> | '''DITHIOL ALPHA MELANOTROPIN PEPTIDE CYCLIZED VIA RHENIUM METAL COORDINATION'''<br /> | ||
==Overview== | ==Overview== | ||
| - | alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through | + | alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind alpha-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, D-Phe7-alpha-MSH4-13 analog. Structural analysis of the Re-peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate-metal-thiolate cyclization. A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re-alpha-MSH analog. Characterization of the second-generation Re-peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained. The corresponding 99mTc- and 188ReCCMSH complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of alpha-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties. |
==About this Structure== | ==About this Structure== | ||
| - | 1B0Q is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with RE, ACE and NH2 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1B0Q is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=RE:'>RE</scene>, <scene name='pdbligand=ACE:'>ACE</scene> and <scene name='pdbligand=NH2:'>NH2</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1B0Q OCA]. |
==Reference== | ==Reference== | ||
Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination., Giblin MF, Wang N, Hoffman TJ, Jurisson SS, Quinn TP, Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12814-8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9788997 9788997] | Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination., Giblin MF, Wang N, Hoffman TJ, Jurisson SS, Quinn TP, Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12814-8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9788997 9788997] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Giblin, M | + | [[Category: Giblin, M F.]] |
| - | [[Category: Hoffman, T | + | [[Category: Hoffman, T J.]] |
| - | [[Category: Jurisson, S | + | [[Category: Jurisson, S S.]] |
| - | [[Category: Quinn, T | + | [[Category: Quinn, T P.]] |
[[Category: Wang, N.]] | [[Category: Wang, N.]] | ||
[[Category: ACE]] | [[Category: ACE]] | ||
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[[Category: rhenium technetium]] | [[Category: rhenium technetium]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:50:20 2008'' |
Revision as of 09:50, 21 February 2008
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DITHIOL ALPHA MELANOTROPIN PEPTIDE CYCLIZED VIA RHENIUM METAL COORDINATION
Overview
alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind alpha-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, D-Phe7-alpha-MSH4-13 analog. Structural analysis of the Re-peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate-metal-thiolate cyclization. A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re-alpha-MSH analog. Characterization of the second-generation Re-peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained. The corresponding 99mTc- and 188ReCCMSH complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of alpha-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties.
About this Structure
1B0Q is a Protein complex structure of sequences from [1] with , and as ligands. Full crystallographic information is available from OCA.
Reference
Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination., Giblin MF, Wang N, Hoffman TJ, Jurisson SS, Quinn TP, Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12814-8. PMID:9788997
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