Interaction of Vanadium Complexes with Proteins: Revisiting the Reported Structures in the Protein Data Bank (PDB) since 2015

Abstract

The structural determination and characterization of molecules, namely proteins and enzymes, is crucial to gaining a better understanding of their role in different chemical and biological processes. The continuous technical developments in the experimental and computational resources of X-ray diffraction (XRD) and, more recently, cryogenic Electron Microscopy (cryo-EM) led to an enormous growth in the number of structures deposited in the Protein Data Bank (PDB). Bioinorganic chemistry arose as a relevant discipline in biology and therapeutics, with a massive number of studies reporting the effects of metal complexes on biological systems, with vanadium complexes being one of the relevant systems addressed. In this review, we focus on the interactions of vanadium compounds (VCs) with proteins. Several types of binding are established between VCs and proteins/enzymes. Considering that the V-species that bind may differ from those initially added, the mentioned structural techniques are pivotal to clarifying the nature and variety of interactions of VCs with proteins and to proposing the mechanisms involved either in enzymatic inhibition or catalysis. As such, we provide an account of the available structural information of VCs bound to proteins obtained by both XRD and/or cryo-EM, mainly exploring the more recent structures, particularly those containing organic-based vanadium complexes.

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“…These findings, needing further experimental corroboration whenever possible, might be at the roots of the inhibitory activity reported in Figure 8, slightly modulated by the nature of the substituents in L and involving a distinct mode of action with respect to Na + (mpo -) and other M-mpo derived species previously examined by our group (Rodriguez Arce et al, 2015;Santos and Pessoa, 2023). The interaction in a distal binding site promotes a structural reorganization in the holoenzyme that starts affecting the cofactor positioning within its binding pocket and ultimately propagates up to the entrance channel, altering the dynamics of the opening/closure to the substrate in the submicroseconds time scale and, for some [V IV O(L-H)(mpo)] such as the one with L = L4, makes NADH unable to adopt the optimal arrangement required at the active site for reducing fumarate to succinate, globally resulting in partial abolition of the catalytic activity.…”

“…Consequently, the complexes [V IV O(L-H)(mpo)] are envisioned to function as pro-drugs. Many structural studies, namely, by single crystal X-ray diffraction, confirm the interaction of vanadium complexes with proteins, as well as the relevance of their partial hydrolysis (Santos and Pessoa, 2023). Namely, crystallographic and theoretical studies addressing the interaction of V IV (8HQ) 2 with bovine pancreatic ribonuclease (RNase A) confirmed the partial hydrolysis of the V IV (8HQ) 2 complex, and the binding of the V IV O(8HQ)(H 2 O) + adduct to the enzyme (Ferraro et al, 2023).…”