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Rational redesign of a cation···π···π stacking at cardiovascular Fbw7-Skp1 complex interface and its application for deriving self-inhibitory peptides to disrupt the complex interaction.

Abstract：

:The Fbw7-Skp1 complex is an essential component in the formation and development of the mammalian cardiovascular system; the complex interaction is mediated through binding of Skp1 C-terminal peptide (qGlu-peptide) to the F-box domain of Fbw7. By visually examining the crystal structure, we identified a typical cation ···π···π stacking system at the complex interface, which is formed by the Trp1159 residue of qGlu-peptide with the Lys2299 and His2359 residues of Fbw7 F-box domain. Both hybrid quantum mechanics/molecular mechanics (QM/MM) analysis of the real domain-peptide complex and electron-correlation ab initio calculation of the stacking system model suggested that the cation···π···π plays an important role in stabilizing the complex; substitution of peptide Trp1159 residue with aromatic Phe and Tyr would not cause a considerable effect on the configuration and energetics of cation···π···π stacking system, whereas His substitution seems to largely destabilize the system. Subsequently, the qGlu-peptide was stripped from the full-length Skp1 protein to define a so-called self-inhibitory peptide, which may rebind to the domain-peptide complex interface and thus disrupt the complex interaction. Fluorescence polarization (FP) assays revealed that the Trp1159Phe and Trp1159Tyr variants have a comparable or higher affinity (K d = 41 and 62 μM) than the wild-type qGlu-peptide (K d = 56 μM), while the Trp1159His mutation would largely impair the binding potency of qGlu-peptide to Fbw7 F-box domain (K d = 280 μM), confirming that the cation···π···π confers both affinity and specificity to the domain-peptide recognition, which can be reshaped by rational molecular design of the nonbonded interaction system. Graphical abstract Stereoview of the complex structure of Fbw7 with Skp1 (PDB: 2ovp), where the Trp1159 residue of Skp1 qGlu-peptide can form a cation···π···π stacking system with the Lys2299 and His2359 residues of Fbw7 F-box domain.

journal_name

J Mol Model

journal_title

Journal of molecular modeling

authors

Zhou J,Wang YS

doi

10.1007/s00894-017-3456-z

subject

Has Abstract

pub_date

2017-09-26 00:00:00

pages

296

issue

eissn

1610-2940

issn

0948-5023

pii

10.1007/s00894-017-3456-z

journal_volume

pub_type

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Rational redesign of a cation···π···π stacking at cardiovascular Fbw7-Skp1 complex interface and its application for deriving self-inhibitory peptides to disrupt the complex interaction.