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Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
RESEARCH ARTICLE

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 (p5317–28) 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 p5317–28 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 (Kd = 105 nM) was determined to exhibit ~5-fold affinity improvement relative to p5317–28 (Kd = 570 nM). In contrast, the binding affinity of the 2Cl-peptide (Kd = 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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