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Multisubstrate Allostery with a Single Helical Switch in Cytochrome P450cam.

Mohammad Sahil1, Jagannath Mondal1

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The I-helix regulates Cytochrome P450cam function by switching between straight and kinked conformations, controlling substrate access and allosteric coupling. This discovery offers a blueprint for engineering P450 enzymes.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzyme Kinetics

Background:

  • Cytochrome P450cam displays complex conformational changes and allostery.
  • A unified mechanism explaining these behaviors has been lacking.

Purpose of the Study:

  • To identify the key regulatory element governing P450cam conformational dynamics and allostery.
  • To elucidate the mechanism of substrate-induced allosteric coupling.

Main Methods:

  • Multimicrosecond molecular dynamics (MD) simulations.
  • Nuclear Magnetic Resonance (NMR) pseudocontact shifts.
  • Ensemble analysis of over 100 crystal structures.

Main Results:

  • The I-helix (αI) acts as a master regulator, transitioning between straight and kinked states.
  • Glycines G248 and G249 provide intrinsic flexibility for these transitions.
  • Substrate binding stabilizes the straight αI conformation, altering solvent channels and allosteric sites.
  • This mechanism explains cooperativity and resolves structural discrepancies.

Conclusions:

  • The I-helix is the central switch for P450cam allostery and function.
  • The G249 residue is conserved in human P450s, suggesting broad relevance.
  • Engineered mutants confirm αI's role as a tunable allosteric switch.
  • This provides a framework for rational P450 engineering.