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

Author

Listed:
  • 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.)

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.

Suggested Citation

  • Stefan Gerhardy & Mark Ultsch & Wanjian Tang & Evan Green & Jeffrey K. Holden & Wei Li & Alberto Estevez & Chris Arthur & Irene Tom & Alexis Rohou & Daniel Kirchhofer, 2022. "Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32760-9
    DOI: 10.1038/s41467-022-32760-9
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    References listed on IDEAS

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    1. Mark S. Dennis & Charles Eigenbrot & Nicholas J. Skelton & Mark H. Ultsch & Lydia Santell & Mary A. Dwyer & Mark P. O'Connell & Robert A. Lazarus, 2000. "Peptide exosite inhibitors of factor VIIa as anticoagulants," Nature, Nature, vol. 404(6777), pages 465-470, March.
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    Cited by:

    1. Yanjie Li & Yuehua Wei & Mark Ultsch & Wei Li & Wanjian Tang & Benjamin Tombling & Xinxin Gao & Yoana Dimitrova & Christian Gampe & Jakob Fuhrmann & Yingnan Zhang & Rami N. Hannoush & Daniel Kirchhofe, 2024. "Cystine-knot peptide inhibitors of HTRA1 bind to a cryptic pocket within the active site region," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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