Academic Journal
Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration
| العنوان: | Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration |
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| المؤلفون: | Gerhardy, Stefan, Ultsch, Mark, Tang, Wanjian, Green, Evan, Holden, Jeffrey K., Li, Wei, Estevez, Alberto, Arthur, Chris, Tom, Irene, Rohou, Alexis, Kirchhofer, Daniel |
| المصدر: | Nature Communications ; volume 13, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2022 |
| الوصف: | The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 Å away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-022-32760-9 |
| الاتاحة: | http://dx.doi.org/10.1038/s41467-022-32760-9 https://www.nature.com/articles/s41467-022-32760-9.pdf https://www.nature.com/articles/s41467-022-32760-9 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.B40F66C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-022-32760-9 |
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