Structural dynamics of cisplatin binding to histidine in a protein

Abstract

The platinum anti-cancer agents cisplatin and carboplatin bind to the histidine 15 residue in the model protein hen egg white lysozyme. By using temperatures either side of the protein glass transition state (∼180 K), several platinum binding modes are seen and show that not all these platinum modes are stable. In particular, the mean square displacement vibration amplitudes of the cisplatin and of the histidine to which it is bound are analysed in detail. As well as the multiple platinum peaks, the electron density for the His-15 side chain is weak to absent at 150 K and 200 K, which points to the imidazole ring of the His side chain sampling multiple positions. Most interestingly, the His-15 imidazole becomes more ordered at room temperature.

Comment on “Structural dynamics of cisplatin binding to histidine in a protein” [Struct. Dyn. 1, 034701 (2014)]

“…We have considered the His 15 imidazole ring split occupancy (60%/40%) placements in 4yeo but conclude that there was insufficient 2Fo-Fc electron density at the1.2 rms contour level and no Fo-Fc electron density contoured at the COOT default cut off of 5σ for such a precise interpretation. But, as we stated in our paper ( Tanley and Helliwell, 2014 ), the His 15 imidazole ring we do agree is taking up multiple positions indicative of the structural dynamics of binding of the cisplatin, as we point out in our article.…”

“…(2015) concur with. The respective platinum atoms' refined occupancies and ADPs are as in 4mwk, which were derived from SHELX least squares model refinements, as described in our article ( Tanley and Helliwell, 2014 ). We also note that the anomalous difference densities for sulphur atoms are very clear and well resolved on the lysozyme molecule disulphides and therefore are confident on the quality of the measured anomalous difference data.…”

“…Since Tanley and Helliwell's (2014) Structural Dynamics article is a comparison of identically prepared crystals' diffraction data measured at three different temperatures, and carboplatin binding in the triclinic crystal form at one temperature, we have also revisited 4mwm, 4mwn, and 4oxe to again (i) remove any clashing solute molecules and (ii) replace the potentially confusing use of the incorrect “CPT.” We have removed solute molecules which we are not certain as to their chemical identities. In all these cases above (4mwk, 4mwm, 4mwn, and 4oxe), the as previously published processed structure factor amplitudes' data have been used.…”

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

“…This is not directly coordinated to protein residues. A Pt 2+ ion was found close to the N-terminal tail also in the adduct formed in the reaction between HEWL and cisplatin by Helliwell and coworkers [22]. formed within crystals of HEWL which were exposed for 6 months to compound 1.…”

Direct Binding of Cisplatin to p22phox, an Endoplasmic Reticulum (ER) Membrane Protein, Contributes to Cisplatin Resistance in Oral Squamous Cell Carcinoma (OSCC) Cells

“…In addition, CDDP could bind to the GA-30 peptide in a time- and dose-dependent manner, further ensuring the binding affinity between these two molecules ( Figure 2 D,E). Furthermore, MA-11, a portion of the GA-30 peptide predictably harboring the “hot-spot” CDDP-binding residues (Met and His) [ 14 , 15 ], was found to be bound to the Pt of CDDP by analyzing the mass-to-charge ( m / z ) values in the liquid chromatography-mass spectrometry (LC–MS) spectrum ( Figure 2 F). Together, these data have conclusively shown the ability of CDDP to platinate the GA-30 domain, possibly leading to the formation of CDDP-p22phox adducts.…”