Abstract
Binding and conformational change of all-trans-retinoic acid (ATRA) with peptidyl prolyl cis/trans isomerase Pin1 were investigated systematically by spectroscopic and computational techniques under experimentally optimized physiological conditions. The intrinsic fluorescence of Pin1 was quenched through a static quenching mechanism in the presence of ATRA with binding constants on the order of 105 mol/L. Thermodynamic parameters (ΔH = 15.76 kJ/mol and ΔS = 158.36 J/mol·K at 293 K) and computational results illustrated that the hydrophobic interactions played a significant role in the binding process of ATRA to Pin1, but electrostatic forces, weak van der Waals, and hydrogen bonds cannot be ignored. Circular dichroism, fluorescence spectra, and computational simulations revealed that ATRA interacted with residues Lys63 and Arg69 of Pin1 to affect its conformational changes. Molecular dynamic simulation, principal component analysis, and free energy landscape monitored the dynamical conformational characteristics of ATRA binding to Pin1. All in all, the present research might provide a reference for the development and design of retinoic acid drugs that inhibit the activity of Pin1.
Highlights
Peptidyl prolyl cis-trans isomerase Pin1 is a unique enzyme that catalyzes cis-trans isomerization of phosphorylated serine/threonine-proline motif and posttranslationally modulates the structure and function of Pin1 substrates [1]
Pin1 binds to pSer246-Pro motif of ß-catenin, inhibits its interaction with adenomatous polyposis coli (APC), and improves its stability and transport to the nucleus [2]. erefore, Pin1 can regulate multiple cancerdriving signaling pathways, such as Wnt/β-catenin, PI3K/AKT, and RTK/Ras/ERK pathway, and some physiological processes, such as cell cycle, apoptosis, and aging [3,4,5]
all-trans-retinoic acid (ATRA) has become the standard front-line drug used for the treatment of acute promyelocytic leukemia (APL) in adults and that of Journal of Spectroscopy
Summary
Peptidyl prolyl cis-trans isomerase Pin is a unique enzyme that catalyzes cis-trans isomerization of phosphorylated serine/threonine-proline (pSer/ r-Pro) motif and posttranslationally modulates the structure and function of Pin substrates [1]. Pin binds to p r286-Pro motif of Cyclin D1 and increases its stability in the nucleus [2]. Pin binds to pSer246-Pro motif of ß-catenin, inhibits its interaction with adenomatous polyposis coli (APC), and improves its stability and transport to the nucleus [2]. ATRA binds to the active pocket of Pin and inhibits its biological function, which induces its degradation in acute promyelocytic leukemia (APL) cells [20]. We utilized multiple spectroscopic and computational techniques to explore the dynamical conformational characteristics of ATRA binding to Pin in an aqueous solution at physiological conditions. E conformational changes of ATRA binding to Pin were determined by synchronous fluorescence, threedimensional (3D) fluorescence, and circular dichroism (CD). Is study would help understand the binding model and inhibition mechanism of Pin1-ATRA complex We utilized multiple spectroscopic and computational techniques to explore the dynamical conformational characteristics of ATRA binding to Pin in an aqueous solution at physiological conditions. e quenching constants (Ksv), binding constants (Ka), the number of binding sites (n), and thermodynamic parameters (ΔH, ΔS, and ΔG) of Pin by ATRA were calculated using fluorescence spectra at different temperatures (293 K and 303 K). e conformational changes of ATRA binding to Pin were determined by synchronous fluorescence, threedimensional (3D) fluorescence, and circular dichroism (CD). e dynamic characteristics of ATRA binding to Pin were monitored at the atomic level by molecular dynamics simulations, principal component analysis, and free energy landscape. is study would help understand the binding model and inhibition mechanism of Pin1-ATRA complex
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