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Rational Design of an Orthogonal Noncovalent Interaction System at the MUPP1 PDZ11 Complex Interface with CaMKIIα-derived Peptides in Human Fertilization

Abstract

The recognition and association between Ca2+/calmodulin-activated protein kinase II-α (CaMKIIα) and multi-PDZ domain protein 1 (MUPP1) plays an important role in sperm acrosome reaction and human fertilization. Previously, we demonstrated that MUPP1 PDZ11 domain is the primary binding partner of CaMKIIα C-terminal tail, which can be targeted by a rationally designed sia peptide with nanomolar affinity. Here, we further introduced an orthogonal noncovalent interaction (ONI) system between a native hydrogen bond and a designed halogen bond across the complex interface of PDZ11 domain with sia [Asn-1Phe] peptide mutant, where the halogen bond was formed by substituting o-hydrogen atom of the benzene ring of peptide Phe-1 residue with a halogen atom (F, Cl, Br or I). Molecular dynamics simulations and high-level theoretical calculations suggested that the bromine (Br) is a good compromise between the halogen-bonding strength and steric hindrance effect due to introducing bulkier halogen atom to the tightly packed complex interface. Fluorescence spectroscopy assays revealed that the resulting o-Br-substituted peptide (Kd = 18 nM) exhibited ~7.6-fold affinity increase relative to its native counterpart (Kd = 137 nM). In contrast, the p-Br-substituted peptide, a negative control that is unable to form the ONI according to structure-based analysis, has a decreased affinity (Kd = 210 nM) upon the halogenation.

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Publication details

The article was received on 19 Jun 2017, accepted on 21 Jul 2017 and first published on 21 Jul 2017


Article type: Paper
DOI: 10.1039/C7MB00379J
Citation: Mol. BioSyst., 2017, Accepted Manuscript
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    Rational Design of an Orthogonal Noncovalent Interaction System at the MUPP1 PDZ11 Complex Interface with CaMKIIα-derived Peptides in Human Fertilization

    Y. Zhang and Z. Han, Mol. BioSyst., 2017, Accepted Manuscript , DOI: 10.1039/C7MB00379J

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