Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Stefan Gerhardy; Mark Ultsch; Wanjian Tang; Evan Green; Jeffrey K. Holden; Wei Li; Alberto Estevez; Chris Arthur; Irene Tom; Alexis Rohou; Daniel Kirchhofer

doi:10.1038/s41467-022-32760-9

Nature Communications (Sep 2022)

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

Stefan Gerhardy,
Mark Ultsch,
Wanjian Tang,
Evan Green,
Jeffrey K. Holden,
Wei Li,
Alberto Estevez,
Chris Arthur,
Irene Tom,
Alexis Rohou,
Daniel Kirchhofer

Affiliations

Stefan Gerhardy: Department of Early Discovery Biochemistry, Genentech Inc.
Mark Ultsch: Department of Structural Biology, Genentech Inc.
Wanjian Tang: Department of Early Discovery Biochemistry, Genentech Inc.
Evan Green: Department of Structural Biology, Genentech Inc.
Jeffrey K. Holden: Department of Early Discovery Biochemistry, Genentech Inc.
Wei Li: Department of Early Discovery Biochemistry, Genentech Inc.
Alberto Estevez: Department of Structural Biology, Genentech Inc.
Chris Arthur: Department of Structural Biology, Genentech Inc.
Irene Tom: Department of OMNI Biomarker Development, Genentech Inc.
Alexis Rohou: Department of Structural Biology, Genentech Inc.
Daniel Kirchhofer: Department of Early Discovery Biochemistry, Genentech Inc.

DOI: https://doi.org/10.1038/s41467-022-32760-9
Journal volume & issue: Vol. 13, no. 1
pp. 1 – 16

Abstract

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The protease HTRA1 is a genetic risk factor for geographic atrophy. Here, Gerhardy et al. describe its inhibition by a clinical Fab, whose binding locks it in an inactive state. The mechanism identifies an essential function of LoopA with this protease family.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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