Cystine-knot peptide inhibitors of HTRA1 bind to a cryptic pocket within the active site region

Li, Yanjie; Wei, Yuehua; Ultsch, Mark; Li, Wei; Tang, Wanjian; Tombling, Benjamin; Gao, Xinxin; Dimitrova, Yoana; Gampe, Christian; Fuhrmann, Jakob; Zhang, Yingnan; Hannoush, Rami N.; Kirchhofer, Daniel

doi:10.1038/s41467-024-48655-w

Cystine-knot peptide inhibitors of HTRA1 bind to a cryptic pocket within the active site region

Journal Article · Wed May 22 00:00:00 EDT 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-024-48655-w· OSTI ID:2469708

Li, Yanjie ^[1]; Wei, Yuehua ^[1]; Ultsch, Mark ^[1]; Li, Wei ^[1]; Tang, Wanjian ^[1]; Tombling, Benjamin ^[1]; Gao, Xinxin ^[1]; Dimitrova, Yoana ^[1]; Gampe, Christian ^[1]; Fuhrmann, Jakob ^[1]; Zhang, Yingnan ^[1]; ^[1]; ^[1]

Genentech, San Francisco, CA (United States)

Cystine-knot peptides (CKPs) are naturally occurring peptides that exhibit exceptional chemical and proteolytic stability. We leveraged the CKP carboxypeptidase A1 inhibitor as a scaffold to construct phage-displayed CKP libraries and subsequently screened these collections against HTRA1, a trimeric serine protease implicated in age-related macular degeneration and osteoarthritis. The initial hits were optimized by using affinity maturation strategies to yield highly selective and potent picomolar inhibitors of HTRA1. Crystal structures, coupled with biochemical studies, reveal that the CKPs do not interact in a substrate-like manner but bind to a cryptic pocket at the S1’ site region of HTRA1 and abolish catalysis by stabilizing a non-competent active site conformation. The opening and closing of this cryptic pocket is controlled by the gatekeeper residue V221, and its movement is facilitated by the absence of a constraining disulfide bond that is typically present in trypsin fold serine proteases, thereby explaining the remarkable selectivity of the CKPs. Our findings reveal an intriguing mechanism for modulating the activity of HTRA1, and highlight the utility of CKP-based phage display platforms in uncovering potent and selective inhibitors against challenging therapeutic targets.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2469708

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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