Issue 26, 2018

A case of extensive protein platination: the reaction of lysozyme with a Pt(ii)–terpyridine complex

Abstract

An antiproliferative platinum(II)–terpyridine complex bearing two piperidine substituents at positions 2 and 2′ (compound 1, hereafter) interacts non-covalently with DNA and induces cell death through necrosis, i.e. a mode of action that is distinct from that exhibited by cisplatin (Suntharalingam, et al., Metallomics, 2013, 5, 514). Here, the interaction between this Pt compound and the model protein hen egg white lysozyme (HEWL) was studied by both electrospray ionization mass spectrometry (ESI MS) and X-ray crystallography. The ESI MS data collected after 24 h protein incubation with compound 1 at two different pH values offer evidence that the metal complex degrades upon reaction with HEWL, forming adducts with 1 : 1, 2 : 1 and 3 : 1 Pt/protein ratios. Two different X-ray structures of Pt–protein adducts, obtained by the reaction of HEWL with the Pt compound under different experimental conditions and incubation times, are then reported. An unexpected extensive platination of the protein is clearly observed: Pt containing fragments bind close to the NZ atom of Lys1 and OE1 atom of Glu7, NE2 atom of His15 and NH1 atom of Arg14, ND1 atom of His15, NZ atom of Lys96, NZ atom of Lys97 and ND1 atom of Asn93, NZ atom of Lys13 and the C-terminal carboxylate, and the N-terminal amine. An additional binding site was observed close to the NZ atom of Lys33. These results suggest that both N- and C-terminal tails, as well as Lys side chains, have to be considered as potential binding sites of Pt-containing drugs. The peculiar reactivity of compound 1 with biological macromolecules could play a role in its mode of action.

Graphical abstract: A case of extensive protein platination: the reaction of lysozyme with a Pt(ii)–terpyridine complex

Supplementary files

Article information

Article type
Paper
Submitted
30 Mar 2018
Accepted
31 May 2018
First published
01 Jun 2018

Dalton Trans., 2018,47, 8716-8723

A case of extensive protein platination: the reaction of lysozyme with a Pt(II)–terpyridine complex

G. Ferraro, T. Marzo, T. Infrasca, A. Cilibrizzi, R. Vilar, L. Messori and A. Merlino, Dalton Trans., 2018, 47, 8716 DOI: 10.1039/C8DT01254G

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements