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{{Theoretical_model}} | {{Theoretical_model}} | ||
< | ==LEU55PRO TTR-IDOX THEORETICAL MODEL== | ||
<StructureSection load='1f64' size='340' side='right'caption='[[1f64]]' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1F64 FirstGlance]. <br> | |||
</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=1f64 FirstGlance], [https://www.ebi.ac.uk/pdbsum/1f64 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1f64 ProSAT]</span></td></tr> | |||
-- | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The crystal structure of the amyloidogenic Leu-55Pro transthyretin (TTR) variant has revealed an oligomer structure that may represent a putative amyloid protofibril [Sebastiao, Saraiva and Damas (1998) J. Biol. Chem. 273, 24715-24722]. Here we report biochemical evidence that corroborates the isolation of an intermediate structure, an 'amyloid-like' oligomer, which is most probably present in the biochemical pathway that leads to amyloid deposition and that was isolated by the crystallization of the Leu-55Pro TTR variant. 4'-Iodo-4'-deoxydoxorubicin (IDOX) is a compound that interacts with amyloid fibrils of various compositions and it has been reported to reduce the amyloid load in immunoglobulin light chain amyloidosis [Merlini, Ascari, Amboldi, Bellotti, Arbustini, Perfetti, Ferrari, Zorzoli, Marinone, Garini et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 2959-2963]. In this work, we observed that the monoclinic Leu-55Pro TTR crystals, soaked with IDOX, undergo rapid dissociation. Moreover, under the same conditions, the orthorhombic wild-type TTR crystals are quite stable. This is explained by the different TTR conformations isolated upon crystallization of the two proteins; while the Leu-55Pro TTR exhibits the necessary conformation for IDOX binding, the same structure is not present in the crystallized wild-type protein. A theoretical model concerning the interaction of Leu-55Pro TTR with IDOX, which is consistent with the dissociation of the amyloid-like oligomer, is presented. In this model the IDOX iodine atom is buried in a pocket located between the two beta-sheets of the Leu-55Pro TTR monomer with the IDOX aromatic-moiety long axis nearly perpendicular to the direction of the beta-sheets. | |||
The molecular interaction of 4'-iodo-4'-deoxydoxorubicin with Leu-55Pro transthyretin 'amyloid-like' oligomer leading to disaggregation.,Sebastiao MP, Merlini G, Saraiva MJ, Damas AM Biochem J. 2000 Oct 1;351(Pt 1):273-9. PMID:10998371<ref>PMID:10998371</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1f64" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Theoretical Model]] | ||
[[Category: Large Structures]] | |||
== | |||
< | |||
[[Category: Sebastiao, M P]] | [[Category: Sebastiao, M P]] | ||
Latest revision as of 12:46, 21 July 2021
 |
LEU55PRO TTR-IDOX THEORETICAL MODELLEU55PRO TTR-IDOX THEORETICAL MODEL
Structural highlights
Publication Abstract from PubMedThe crystal structure of the amyloidogenic Leu-55Pro transthyretin (TTR) variant has revealed an oligomer structure that may represent a putative amyloid protofibril [Sebastiao, Saraiva and Damas (1998) J. Biol. Chem. 273, 24715-24722]. Here we report biochemical evidence that corroborates the isolation of an intermediate structure, an 'amyloid-like' oligomer, which is most probably present in the biochemical pathway that leads to amyloid deposition and that was isolated by the crystallization of the Leu-55Pro TTR variant. 4'-Iodo-4'-deoxydoxorubicin (IDOX) is a compound that interacts with amyloid fibrils of various compositions and it has been reported to reduce the amyloid load in immunoglobulin light chain amyloidosis [Merlini, Ascari, Amboldi, Bellotti, Arbustini, Perfetti, Ferrari, Zorzoli, Marinone, Garini et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 2959-2963]. In this work, we observed that the monoclinic Leu-55Pro TTR crystals, soaked with IDOX, undergo rapid dissociation. Moreover, under the same conditions, the orthorhombic wild-type TTR crystals are quite stable. This is explained by the different TTR conformations isolated upon crystallization of the two proteins; while the Leu-55Pro TTR exhibits the necessary conformation for IDOX binding, the same structure is not present in the crystallized wild-type protein. A theoretical model concerning the interaction of Leu-55Pro TTR with IDOX, which is consistent with the dissociation of the amyloid-like oligomer, is presented. In this model the IDOX iodine atom is buried in a pocket located between the two beta-sheets of the Leu-55Pro TTR monomer with the IDOX aromatic-moiety long axis nearly perpendicular to the direction of the beta-sheets. The molecular interaction of 4'-iodo-4'-deoxydoxorubicin with Leu-55Pro transthyretin 'amyloid-like' oligomer leading to disaggregation.,Sebastiao MP, Merlini G, Saraiva MJ, Damas AM Biochem J. 2000 Oct 1;351(Pt 1):273-9. PMID:10998371[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References |
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