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Radicals: Your Life is in their Hands RNR as a Paradigm

Ribonucleotide reductases (RNRs) catalyze the de novo reduction of NDPs to dNDPs in all organisms, controlling their relative ratios and amounts and contributing to the fidelity of DNA replication and repair. The class Ia RNRs are composed of a2 and b2 subunits that form an active and dynamic a2b2 complex. Studies with mechanism-based inhibitors have revealed half-sites reactivity with only one equivalent of inhibitor required per a2b2 for enzyme inactivation. Studies with unnatural amino acid 2,3,5-F3Y, replacing the essential Y122• in b2 within the 35 angstrom radical transfer (RT) pathway [(•Y122-Y356 )-b2 across the subunit interface to (Y730-Y731-C439)-a2], also reveal half-sites reactivity. When 2,3,5-F3Y122•-b, is incubated with a2, substrate [GDP], and effector (TTP), the conformational gating that rate-limits nucleotide reduction and RT chemistry results in radical-trapping at Y356 within the RT pathway and formation of a tightened “a2b2” complex that has resulted in the first structure of an active RNR. An asymmetric interaction within the active “a2b2” complex and the entire RT pathway is revealed for the first time.

Speaker: JaOAnne Stubbe, MIT

Monday, 12/09/19


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Stanley Hall

UC Berkeley
Room 106
Berkeley, CA 94720