TY - BOOK

T1 - Dynamics of a Highly Flexible Protein

AU - Andersen, Lisbeth

PY - 2014

Y1 - 2014

N2 - Protein dynamics are important for protein function. Especially, dynamics plays an important role in ligand-binding where the induced fit and conformational selection binding mechanisms represent the extremes in a continuum of dynamic mechanisms. The difference between the mechanisms lies in the sequence of events; either the protein changes it conformation after initial binding of the ligand (induced fit) or before binding of the ligand (conformational selection). The nuclear co-activator binding domain (NCBD) interacts with many different binding partners to control gene transcription. High-resolution structures of NCBD in complex with four binding partners are currently known and while three of them are practically identical and resemble the major conformation in the unbound ensemble, one shows NCBD adopting an alternative and markedly different conformation. The mechanisms underlying this conformational malleability are the subject of this defense. Using nuclear magnetic resonance (NMR) spectroscopy, the dynamics of NCBD have been investigated on timescales ranging from picoseconds to milliseconds using relaxation dispersion experiments, residual dipolar couplings and methyl group deuterium relaxation. From this it was found that NCBD is in conformational exchange with an excited state; that several conformations should be included in the native state ensemble of unbound NCBD; and that the dynamics of ligand-bound NCBD is dependent on which ligand is bound.

AB - Protein dynamics are important for protein function. Especially, dynamics plays an important role in ligand-binding where the induced fit and conformational selection binding mechanisms represent the extremes in a continuum of dynamic mechanisms. The difference between the mechanisms lies in the sequence of events; either the protein changes it conformation after initial binding of the ligand (induced fit) or before binding of the ligand (conformational selection). The nuclear co-activator binding domain (NCBD) interacts with many different binding partners to control gene transcription. High-resolution structures of NCBD in complex with four binding partners are currently known and while three of them are practically identical and resemble the major conformation in the unbound ensemble, one shows NCBD adopting an alternative and markedly different conformation. The mechanisms underlying this conformational malleability are the subject of this defense. Using nuclear magnetic resonance (NMR) spectroscopy, the dynamics of NCBD have been investigated on timescales ranging from picoseconds to milliseconds using relaxation dispersion experiments, residual dipolar couplings and methyl group deuterium relaxation. From this it was found that NCBD is in conformational exchange with an excited state; that several conformations should be included in the native state ensemble of unbound NCBD; and that the dynamics of ligand-bound NCBD is dependent on which ligand is bound.

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/1pioq0f/alma99122515775105763

M3 - Ph.D. thesis

BT - Dynamics of a Highly Flexible Protein

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -