2qgb: Difference between revisions
No edit summary |
No edit summary |
||
| Line 2: | Line 2: | ||
caption="2qgb, resolution 1.400Å" /> | caption="2qgb, resolution 1.400Å" /> | ||
'''Human transthyretin (TTR) in Apo-form'''<br /> | '''Human transthyretin (TTR) in Apo-form'''<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== | ||
2QGB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QGB OCA]. | 2QGB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QGB 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]] | ||
| Line 12: | Line 18: | ||
[[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 08:14:26 2008'' | ||
Revision as of 09:14, 13 February 2008
|
Human transthyretin (TTR) in Apo-form
OverviewOverview
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 StructureAbout this Structure
2QGB is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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:18095641
Page seeded by OCA on Wed Feb 13 08:14:26 2008