Rational Design of an Orthogonal Molecular Interaction System at the Complex Interface of Lung Cancer-Related MDM2 Protein with p53 Peptide

Yanwen Li; Xiyan Yu; Ying Lou; Tong Wang

doi:10.1071/CH16096

RESEARCH ARTICLE

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Rational Design of an Orthogonal Molecular Interaction System at the Complex Interface of Lung Cancer-Related MDM2 Protein with p53 Peptide

Yanwen Li ^A ^B , Xiyan Yu ^A , Ying Lou ^A and Tong Wang ^A

+ Author Affiliations

- Author Affiliations

^A Emergency Department of Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.

^B Corresponding author. Email: yanwwenli@126.com

Australian Journal of Chemistry 69(10) 1167-1171 https://doi.org/10.1071/CH16096
Submitted: 20 February 2016 Accepted: 11 April 2016 Published: 3 May 2016

Abstract

The oncogenic protein MDM2 is an important negative regulator of p53 tumour suppressor. Overexpression of this protein is closely related to the pathological progression and metastasis of lung cancer and other tumours. Previously, a 12-mer peptide segment ¹⁷ETFSDLWKLLPE²⁸ (p53^17–28) corresponding to residues 17–28 of the human p53 transactivation domain was identified to interact moderately with MDM2. Here, we successfully created an orthogonal molecular interaction system between a native hydrogen bond (H-bond) and a designed halogen bond (X-bond) across the protein–peptide complex interface, where the X-bond was introduced by substituting the 3-hydrogen atom of the benzene ring of the p53^17–28 Phe19 residue with a halogen atom X, resulting in a series of ³X-peptides (X = F, Cl, Br or I). Theoretical analysis found that chlorine is a good compromise between X-bonding strength and steric hindrance due to introducing a bulkier halogen atom to the tightly packed complex interface. Consequently, the ³Cl-peptide (K_d = 105 nM) was determined to exhibit ~5-fold affinity improvement relative to p53^17–28 (K_d = 570 nM). In contrast, the binding affinity of the ²Cl-peptide (K_d = 492 nM), a negative control that cannot form the X-bond according to computational analysis, did not change considerably on the halogenation.

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Rational Design of an Orthogonal Molecular Interaction System at the Complex Interface of Lung Cancer-Related MDM2 Protein with p53 Peptide

Abstract

References

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