2QGD

Human transthyretin (TTR) complexed with 2-(3,5-Dibromo-4-hydroxyphenyl)benzoxazole

Summary for 2QGD

• Entry DOI: 10.2210/pdb2qgd/pdb
• Descriptor: Transthyretin, 4-(1,3-BENZOXAZOL-2-YL)-2,6-DIBROMOPHENOL (3 entities in total)
• Functional Keywords: transthyretin, tetramer, amyloidogenesis inhibitors, hormone-growth factor complex, hormone/growth factor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 28292.74

Authors

Connelly, S.,Wilson, I.A. (deposition date: 2007-06-28, release date: 2008-02-05, Last modification date: 2023-08-30)

Primary citation

Johnson, S.M.,Connelly, S.,Wilson, I.A.,Kelly, J.W.
Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors.
J.Med.Chem., 51:260-270, 2008

PubMed Abstract: 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.

PubMed: 18095641
DOI: 10.1021/jm0708735

Experimental method

X-RAY DIFFRACTION (1.5 Å)