Fine-tuning the extent and dynamics of binding cleft opening as a potential general regulatory mechanism in parvulin-type peptidyl prolyl isomerases

Abstract

Parvulins or rotamases form a distinct group within peptidyl prolyl cis-trans isomerases. Their exact mode of action as well as the role of conserved residues in the family are still not unambiguously resolved. Using backbone S2 order parameters and NOEs as restraints, we have generated dynamic structural ensembles of three distinct parvulins, SaPrsA, TbPin1 and CsPinA. The resulting ensembles are in good agreement with the experimental data but reveal important differences between the three enzymes. The largest difference can be attributed to the extent of the opening of the substrate binding cleft, along which motional mode the three molecules occupy distinct regions. Comparison with a wide range of other available parvulin structures highlights structural divergence along the bottom of the binding cleft acting as a hinge during the opening-closing motion. In the prototype WW-domain containing parvulin, Pin1, this region is also important in forming contacts with the WW domain known to modulate enzymatic activity of the catalytic domain. We hypothesize that modulation of the extent and dynamics of the identified ‘breathing motion’ might be one of the factors responsible for functional differences in the distinct parvulin subfamilies.

Different modes of barrel opening suggest a complex pathway of ligand binding in human gastrotropin

“…This indicates that our ensembles of the complex state exhibit a more pronounced opening along PC1 than the structure obtained by conventional NMR calculations. The phenomenon that dynamic ensembles, corresponding reasonably well to experimental data ‘magnify’ the differences between different states has been observed in previous works [46]. This magnification is likely a consequence of the ensemble-based treatment of NOE restraints allowing more conformational freedom than conventional structure calculations.…”

Structural ensembles based on NMR parameters suggest a complex pathway of ligand binding in human gastrotropin

“…This indicates that our ensembles of the complex 257 state exhibit a more pronounced opening along PC1 than the structure obtained by 258 conventional NMR calculations. The phenomenon that dynamic ensembles, corresponding 259 reasonably well to experimental data 'magnify' the differences between different states has 260 been observed in previous works [44] and is likely a consequence of the ensemble-based 261 treatment of NOE restraints allowing more conformational freedom than conventional 262 structure calculations, as well as the different balance between the force field and 263 experimental restraints than in conventional structure calculation methods. 264 265 The apo and holo states exhibit characteristic differences in their hydrogen bond pattern as 269 well ( Fig 2B), (Table 2) and (S1 Table).…”

Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures

“…In our calculations no NOE restraints were used that generally confine the sampled conformations to be close to the experimentally determined state. In addition, S restraining primarily restricts the directions and not necessarily the amplitude of motions at given sites [ 39 ]. Therefore, our ensembles might represent motions somewhat scaled up relative to the actual ps-ns dynamics of the PDZ3 domain.…”