2RUR

Solution structure of Human Pin1 PPIase C113S mutant

Summary for 2RUR

• Entry DOI: 10.2210/pdb2rur/pdb
• Related: 2RUQ
• NMR Information: BMRB: 11588
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (1 entity in total)
• Functional Keywords: cys-113 mutation, human pin1 ppiase, isomerase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q13526
• Total number of polymer chains: 1
• Total formula weight: 13105.67

Authors

Jing, W.,Tochio, N.,Tate, S. (deposition date: 2015-01-20, release date: 2016-01-06, Last modification date: 2024-05-15)

Primary citation

Wang, J.,Tochio, N.,Kawasaki, R.,Tamari, Y.,Xu, N.,Uewaki, J.,Utsunomiya-Tate, N.,Tate, S.
Allosteric Breakage of the Hydrogen Bond within the Dual-Histidine Motif in the Active Site of Human Pin1 PPIase
Biochemistry, 54:5242-5253, 2015

PubMed Abstract: Intimate cooperativity among active site residues in enzymes is a key factor for regulating elaborate reactions that would otherwise not occur readily. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is the phosphorylation-dependent cis-trans peptidyl-prolyl isomerase (PPIase) that specifically targets phosphorylated Ser/Thr-Pro motifs. Residues C113, H59, H157, and T152 form a hydrogen bond network in the active site, as in the noted connection. Theoretical studies have shown that protonation to thiolate C113 leads to rearrangement of this hydrogen bond network, with switching of the tautomeric states of adjacent histidines (H59 and H157) [Barman, A., and Hamelberg, D. (2014) Biochemistry 53, 3839-3850]. This is called the "dual-histidine motif". Here, C113A and C113S Pin1 mutants were found to alter the protonation states of H59 according to the respective residue type replaced at C113, and the mutations resulted in disruption of the hydrogen bond within the dual-histidine motif. In the C113A mutant, H59 was observed to be in exchange between ε- and δ-tautomers, which widened the entrance of the active site cavity, as seen by an increase in the distance between residues A113 and S154. The C113S mutant caused H59 to exchange between the ε-tautomer and imidazolium while not changing the active site structure. Moreover, the imidazole ring orientations of H59 and H157 were changed in the C113S mutant. These results demonstrated that a mutation at C113 modulates the hydrogen bond network dynamics. Thus, C113 acts as a pivot to drive the concerted function among the residues in the hydrogen bond network, as theoretically predicted.

PubMed: 26226559
DOI: 10.1021/acs.biochem.5b00606

Experimental method

SOLUTION NMR