Structural insights into DHODH-mediated catalysis and drug resistance. (PubMed, bioRxiv) - Oct 2, 2026 - "To map the functional landscape underlying DHODH inhibitor resistance, we performed deep mutational scanning drug-resistance screens with two clinically-relevant structurally distinct DHODH inhibitors, BAY2402234 and brequinar. Resistance variants cluster in the inhibitor binding site and at a previously unappreciated surface pocket on DHODH that allosterically regulates ubiquinone binding. Together, our findings provide structural evidence for the 'ping pong' model of catalysis, define the mutational landscape governing inhibitor resistance, and reveal novel structural vulnerabilities in DHODH that can be utilized for future drug development."
Journal • Immunology • Infectious Disease • Oncology
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Anders Friberg; David E Root; Hanna Meyer; Hyuk-Soo Seo; Jillian K O'Neil; Judith Günther; Julie-Aurore Losman; Komal Chauhan; Laura Evans; Marcia C Haigis; Marco Mravic; Matthew Vander Heiden; Mio Murakoso; Robert E Lintner; Ruchika Pokhriyal; Shakchhi Joshi; Sirano Dhe-Paganon; Sonia E Trojan; Sven Christian; Sven Giese; Xiaoping Yang
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