2qgc: Difference between revisions
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caption="2qgc, resolution 1.300Å" /> | caption="2qgc, resolution 1.300Å" /> | ||
'''Human transthyretin (TTR) complexed with 2-(3,5-Dimethyl-4-hydroxyphenyl)benzoxazole'''<br /> | '''Human transthyretin (TTR) complexed with 2-(3,5-Dimethyl-4-hydroxyphenyl)benzoxazole'''<br /> | ||
==Overview== | |||
To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also, display high binding selectivity in blood, it proves useful to, systematically optimize each of the three substructural elements that, comprise a typical inhibitor: the two aryl rings and the linker joining, them. In the first study, described herein, structural modifications to, one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles, bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several, potent and highly selective amyloidogenesis inhibitors were identified, that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding., High resolution crystal structures (1.3-1.5 A) of three inhibitors ( 2f, 4f, and 4d) in complex with TTR were obtained to characterize their, binding orientation. Collectively, the results demonstrate that thyroid, hormone-like substitution patterns on one aryl ring lead to potent and, highly selective TTR amyloidogenesis inhibitors that lack undesirable, thyroid hormone receptor or COX-1 binding. | |||
==About this Structure== | ==About this Structure== | ||
2QGC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MR4:'>MR4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Known structural/functional Sites: <scene name='pdbsite=AC1:Mr4+Binding+Site+For+Residue+A+128'>AC1</scene> and <scene name='pdbsite=AC2:Mr4+Binding+Site+For+Residue+B+128'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QGC OCA]. | 2QGC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MR4:'>MR4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Known structural/functional Sites: <scene name='pdbsite=AC1:Mr4+Binding+Site+For+Residue+A+128'>AC1</scene> and <scene name='pdbsite=AC2:Mr4+Binding+Site+For+Residue+B+128'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QGC OCA]. | ||
==Reference== | |||
Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors., Johnson SM, Connelly S, Wilson IA, Kelly JW, J Med Chem. 2008 Jan 24;51(2):260-70. Epub 2007 Dec 21. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18095641 18095641] | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: transthyretin]] | [[Category: transthyretin]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:14:27 2008'' | ||
