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 and Daniel Kirchhofer ()
Additional contact information
Stefan Gerhardy: Genentech Inc.
Mark Ultsch: Genentech Inc.
Wanjian Tang: Genentech Inc.
Evan Green: Genentech Inc.
Jeffrey K. Holden: Genentech Inc.
Wei Li: Genentech Inc.
Alberto Estevez: Genentech Inc.
Chris Arthur: Genentech Inc.
Irene Tom: Genentech Inc.
Alexis Rohou: Genentech Inc.
Daniel Kirchhofer: Genentech Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32760-9

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