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- W3204602702 abstract "ABSTRACT Structural biology is the foundation for deriving molecular mechanisms, where snapshots of macromolecules and binding partners inform on mutations that test or modify function. However, frequently, the impact of mutations violates the underpinnings of structural models, and mechanisms become cryptic. This conundrum applies to multidomain enzymatic systems called nonribosomal peptide synthetases (NRPSs), which assemble simple substrates into complex metabolites often with pharmaceutical properties. Engineering NRPSs can generate new pharmaceuticals 1-3 but a dynamic domain organization challenges rational design. 4-8 Using nuclear magnetic resonance (NMR), we determined the solution structure of a 52 kDa cyclization domain and demonstrate that global intra-domain dynamics enable sensing of substrates tethered to partner domains and draw an allosteric response encompassing the enzyme’s buried active site and two binding sites 40 Å apart. We show that a point-site mutation that impedes the domain dynamics globally hampers the allosteric response. We demonstrate this mechanism through NMR experiments that provide atomic-level read-outs of allosteric responses during biochemical transformations in situ . Our results establish global structural dynamics as sensors of molecular events that can remodel domain interactions and illustrate the need for integrating structural dynamics explicitly when deriving molecular mechanisms through mutagenesis and structural biology." @default.
- W3204602702 created "2021-10-11" @default.
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- W3204602702 date "2021-10-07" @default.
- W3204602702 modified "2023-10-10" @default.
- W3204602702 title "Global Dynamics as Communication Sensors in Peptide Synthetase Cyclization Domains" @default.
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- W3204602702 doi "https://doi.org/10.1101/2021.10.06.461881" @default.
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