ProteinLigand Interactions: Induced Fit

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Protein-Ligand InteractionsInduced Fit

• Jan Bollen

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Overview

• Introduction
• Protein folding and Binding Mechanisms
• Hinge-bending Conformational Transitions
• Allosteric and Nonallosteric Enzymes
• Functional Groups and Binding Epitopes
• Conclusion

3
Overview

• Introduction
• Protein folding and Binding Mechanisms
• Hinge-bending Conformational Transitions
• Allosteric and Nonallosteric Enzymes
• Functional Groups and Binding Epitopes
• Conclusion

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Introduction

• Lock and Key (Emil Fischer, end 20th century)
• Induced Fit (Koshland, 1958)
• Within the new view of protein folding
• (Dill and Chan, 1997)

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Introduction

• Lock and Key (Emil Fischer, end 20th century)
• Best illustrated by enzyme substrate-binding
  process
• Active site rigid en sturdy lock
• Active site exact fit to only one key
  (substrate).

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Introduction

• Induced Fit (Koshland, 1958)
• Proteins no rigid locks
• Accommodate the substrate by adapting the binding
  site

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Introduction

• New View of protein folding (Dill and Chan,
  1997)

• Energy Funnels
• Energy VS conformation
• U1 and U2 fold by proceeding directly down the
  walls of the funnel to the native state
• U3 first forms an intermediate state, that must
  then be unfolded before the protein can reach N
• Unfolding requires energy be put into the
  protein so that it can escape that
  particular "pit", and thus intermediates
  represent traps.

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Introduction

• Allosteric and non allosteric enzymes

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Introduction

• Within the new view of protein folding (Dill
  and Chan, 1997)
• Protein-ligand complex fusion between the energy
  landscapes
• In reality more rugged landscapes
• degree of rugged depends on flexibility of
  P/L/P-L
• For binding mechanisms focus on the bottoms of
  the funnels
• Rigid proteins single/few minima
• Flexible proteins rugged, with low barriers,
  corresponds to a range of conformations.

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Overview

• Introduction
• Protein folding and Binding Mechanisms
• Hinge-bending Conformational Transitions
• Allosteric and Nonallosteric Enzymes
• Conclusion

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Protein folding and Binding Mechanisms

• Binding mechanism
• assigned via a comparison of the structures of
• the crystallized bound conformer
• the crystallized unbound conformational isomer
• Difference between the conformers (backbone)
• Small lock and key
• Big Induced fit
• But, the difference between the conformers does
  not necessarily mean induced fit
• Why?
• Crystal of bound bound to the ligand
• Crystal of unboud also bound but to its twin
  molecule

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Protein folding and Binding Mechanisms

• Binding mechanism
• No need to invoke lock and key or the induced
  fit!
• Consider the variability of the conformers.
• In all cases the conformer that binds is the one
  most favorable and complementary
• Different conformers may well bind different
  ligands
• Thus, the larger the flexibility, the wider the
  scope of binding specificity
• Nevertheless, in solution sidechains move, some
  induced fit is not precluded, optimizing the
  receptor-ligand interactions.

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Overview

• Introduction
• Protein folding and Binding Mechanisms
• Hinge-bending Conformational Transitions
• Allosteric and Nonallosteric Enzymes
• Conclusion

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Hinge-bending Conformational Transitions

• No detail, can also be explained by funnels

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Overview

• Introduction
• Protein folding and Binding Mechanisms
• Hinge-bending Conformational Transitions
• Allosteric and Nonallosteric Enzymes
• Conclusion

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Allosteric and Nonallosteric Enzymes

• The majority of the conformational changes in
  allosteric regulation involve subunit motions.
• Binding of the inhibitor favours the T state.
• Binding of the activator favours the R state.
• Allostery is related to the concept of funnels.
• But, as the system is larger, and more
  conformations are possible, the funnels will be
  more complex.
• The bottom of the folding funnels are populated
  by ensemble of conformations of single proteins.
• The bottom of the binding funnels by an ensemble
  of bound conformations.

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Allosteric and Nonallosteric Enzymes

• For allosterically regulated proteins, there are
  additional considerations.
• First, allostery is often observed in a
  quaternary molecular assembly, involving several
  subunits.
• Second, the binding of the inducer needs to be
  considered, in addition to the substrate.
• ?Hence, allostery involves large multimolecular
  complexes, with higherdimensional, complex
  funnels.

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Overview

• Introduction
• Protein folding and Binding Mechanisms
• Hinge-bending Conformational Transitions
• Allosteric and Nonallosteric Enzymes
• Conclusion

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Conclusion

• The new view of protein folding can be extended
  to explain the concepts behind the theories of
  Induced Fit and Lock and Key binding.
• The energy funnel is equally useful in
  understanding protein function.