title: Two pathways mediate interdomain allosteric regulation in pin1.
abstract: Allostery is an essential means for regulating biomolecular functions and provides unique opportunities for drug design, yet our ability to elucidate allosteric mechanisms remains limited. Here, based on extensive molecular dynamics simulations, we present an atomistic picture of the pathways mediating the allosteric regulation of the PPIase domain of Pin1 by its WW domain. Two pathways jointly propagate the action of substrate-WW binding to produce closure and rigidification of three PPIase catalytic-site loops. One pathway preexists in the apo protein, but remains dormant until substrate-WW binding completes the second. The reduction in conformational entropy and preorganization of the catalytic-site loops observed here may explain why substrate-WW binding enhances ligand affinity and catalytic activity of the PPIase domain and suggest a combination drug therapy for Pin1-related diseases. Whereas the traditional view of allostery has emphasized conformational transition, our study identifies a distinct role of conformational dynamics in eliciting allostery.
authors.affiliation: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA; Department of Chemistry, School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Pang
authors.affiliation: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA. Electronic address: hzhou4@fsu.edu.
authors.forename: Huan-Xiang
authors.initials: HX
authors.lastname: Zhou
mesh_terms: D000494:Allosteric Regulation; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase