PDBsum entry 4z41

Hydrolase

PDB id: 4z41

Contents

Protein chain

129 a.a.

Ligands

4KV

DMS

NO3 ×6

EDO ×5

Waters ×100

PDB id:

4z41

Name:

Hydrolase

Title:

X-ray structure of the adduct formed in the reaction between lysozyme and a platinum(ii) compound with a s,o bidentate ligand (9a=chloro- (1-(3'-hydroxy)-3-(methylthio)-3-thioxo-prop-1-en-1-olate-o,s)- (dimethylsulfoxide-s)-platinum(ii))

Structure:

LysozymE C. Chain: a. Synonym: 1,4-beta-n-acetylmuramidasE C,allergen gal d iv. Ec: 3.2.1.17

Source:

Gallus gallus. Chicken. Organism_taxid: 9031

Resolution:

1.89Å R-factor: 0.166 R-free: 0.219

Authors:

A.Merlino

Key ref:

C.Mügge et al. (2015). Platinum(II) Complexes with O,S Bidentate Ligands: Biophysical Characterization, Antiproliferative Activity, and Crystallographic Evidence of Protein Binding. Inorg Chem, 54, 8560-8570. PubMed id: 26280387 DOI: 10.1021/acs.inorgchem.5b01238

Date:

01-Apr-15 Release date: 02-Sep-15

Protein chain

P00698  (LYSC_CHICK) -  Lysozyme C from Gallus gallus

Seq: 147 a.a.

Struc: 129 a.a.

Enzyme reactions

• Enzyme class: E.C.3.2.1.17 - lysozyme.
• Reaction: Hydrolysis of the 1,4-beta-linkages between N-acetyl-D-glucosamine and N-acetylmuramic acid in peptidoglycan heteropolymers of the prokaryotes cell walls.

DOI no: 10.1021/acs.inorgchem.5b01238

Inorg Chem 54:8560-8570 (2015)

PubMed id: 26280387

Platinum(II) Complexes with O,S Bidentate Ligands: Biophysical Characterization, Antiproliferative Activity, and Crystallographic Evidence of Protein Binding.

C.Mügge, T.Marzo, L.Massai, J.Hildebrandt, G.Ferraro, P.Rivera-Fuentes, N.Metzler-Nolte, A.Merlino, L.Messori, W.Weigand.

ABSTRACT

We recently characterized a series of novel platinum(II) compounds bearing a conserved O,S binding moiety as a bifunctional ligand and evaluated their solution behavior and antiproliferative properties in vitro against a representative cancer cell line. On the whole, those platinum compounds showed an appreciable stability in mixed dimethyl sulfoxide-aqueous buffers and promising in vitro cytotoxic effects; yet they manifested a rather limited solubility in aqueous media making them poorly suitable for further pharmaceutical development. To overcome this drawback, four new derivatives of this series were prepared and characterized based on a careful choice of substituents on the O,S bidentate ligand. The solubility and stability profile of these novel compounds in a reference buffer was determined, as well as the ligands' log Po/w value (Po/w = n-octanol-water partition coefficient) as an indirect measure for the complexes' lipophilicity. The antiproliferative properties were comparatively evaluated in a panel of three cancer cell lines. The protein binding properties of the four platinum compounds were assessed using the model protein hen egg white lysozyme (HEWL), and the molecular structures of two relevant HEWL-metallodrug adducts were solved. Overall, it is shown that a proper choice of the substituents leads to a higher solubility and enables a selective fine-tuning of the antiproliferative properties. The implications of these results are thoroughly discussed.