Молекулярные механизмы регуляции рецептора тиреотропного гормона – от сигналинга к разработке лекарств

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Аннотация

Рецептор тиреотропного гормона (ТТГ), с которым специфически связываются ТТГ и тиреостимулин, является ключевым компонентом тиреоидной системы, контролирующей широкий спектр жизненно важных процессов в организме человека и позвоночных животных. Этот рецептор структурно близок рецепторам гонадотропинов. Он также имеет значительный по размеру эктодомен с расположенным в нем ортостерическим сайтом для связывания ТТГ, трансмембранный домен, который взаимодействует с гетеротримерными G-белками и β-аррестинами и во внутренней полости которого локализованы аллостерические сайты и способен к образованию функционально активных гомоди(олиго)мерных комплексов. При патологии на внеклеточные участки рецептора ТТГ вырабатываются антитела с различным профилем биологической активности, вызывающие аутоиммунные заболевания щитовидной железы. Эффективность взаимодействия ТТГ с ортостерическим сайтом и избирательность стимуляции определенного внутриклеточного каскада контролируются целым рядом аллостерических механизмов и регуляторов, среди которых статус N-гликозилирования молекул ТТГ, комплексообразование рецептора ТТГ, локализация в его шарнирной петле «внутреннего» агониста, липидный состав мембраны. Настоящий обзор посвящен механизмам ортостерической и аллостерической регуляции активности рецептора ТТГ, их взаимосвязям, а также роли изменений активности рецептора ТТГ в развитии аутоиммунных заболеваний и рака щитовидной железы, офтальмопатии Грейвса, остеопороза. 
В нем также рассмотрены достижения в разработке низкомолекулярных аллостерических регуляторов рецептора ТТГ и перспективы их возможного использования в медицине.

Об авторах

А. О. Шпаков

Федеральное государственное бюджетное учреждение науки Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН

Email: alex_shpakov@list.ru
заместитель директора, заведующий лабораторией, д.б.н. Санкт-Петербург, 194223

К. В. Деркач

Федеральное государственное бюджетное учреждение науки Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН

Email: derkatch_k@list.ru
ведущий научный сотрудник, к.б.н. Санкт-Петербург, 194223

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