10.4225/03/57428DF17B655 SP Bottomley SP Bottomley Ashley Buckle Ashley Buckle RE Butcher RE Butcher LD Cabrita LD Cabrita KF Fulton KF Fulton JA Irving JA Irving AM Lesk AM Lesk SL Reeve SL Reeve Jamie Rossjohn Jamie Rossjohn I Smith I Smith James Whisstock James Whisstock The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition. Monash University 2016 serpine Peptide Hydrolases ImagingLocus Molecular Biology Biochemistry 2016-12-11 22:57:39 Dataset https://bridges.monash.edu/articles/dataset/The_high_resolution_crystal_structure_of_a_native_thermostable_serpin_reveals_the_complex_mechanism_underpinning_the_stressed_to_relaxed_transition_/3123022 Serpins fold into a native metastable state and utilize a complex conformational change to inhibit target proteases. An undesirable result of this conformational flexibility is that most inhibitory serpins are heat sensitive, forming inactive polymers at elevated temperatures. However, the prokaryote serpin, thermopin, from Thermobifida fusca is able to function in a heated environment. We have determined the 1.8 A x-ray crystal structure of thermopin in the native, inhibitory conformation. A structural comparison with the previously determined 1.5 A structure of cleaved thermopin provides detailed insight into the complex mechanism of conformational change in serpins. Flexibility in the shutter region and electrostatic interactions at the top of the A beta-sheet (the breach) involving the C-terminal tail, a unique structural feature of thermopin, are postulated to be important for controlling inhibitory activity and triggering conformational change, respectively, in the native state. Here we have discussed the structural basis of how this serpin reconciles the thermodynamic instability necessary for function with the stability required to withstand elevated temperatures.<br>