Metal–ligand interactions: An analysis of zinc binding groups using the Protein Data Bank

Kawai, Kentaro; Nagata, Naoto

doi:10.1016/j.ejmech.2012.02.028

Cited by 41 publications

(41 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2,3 In the majority of these examples, the small molecule inhibitors possess functional groups that bind to the active site metal ion of the enzyme; 4 a relatively small selection of such groups, including carboxylates, phosphates, and hydroxamic acids, are commonly employed as the metal-binding groups (MBGs) of choice. 5 Recently, a number of efforts have focused on the development of alternative MBGs to these commonly employed groups, 6 and indeed some newer metalloprotein inhibitors, such as raltegravir and dolutegravir against HIV integrase (HIV1 IN, Mg 2+ -dependent), employ more sophisticated heterocyclic MBGs. 7–9 These next-generation MBGs have the potential to improve the potency, selectivity, and pharmacokinetics of metalloprotein-targeted therapeutics.…”

Section: Introductionmentioning

confidence: 99%

‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site

Martin

Blachly²,

Marts

et al. 2014

J. Am. Chem. Soc.

View full text Add to dashboard Cite

The binding of three closely related chelators: 5-hydroxy-2-methyl-4H-pyran-4-thione (allothiomaltol, ATM), 3-hydroxy-2-methyl-4H-pyran-4-thione (thiomaltol, TM), and 3-hydroxy-4H-pyran-4-thione (thiopyromeconic acid, TPMA) to the active site of human carbonic anhydrase II (hCAII) has been investigated. Two of these ligands display a monodentate mode of coordination to the active site Zn2+ ion in hCAII that is not recapitulated in model complexes of the enzyme active site. This unprecedented binding mode in the hCAII-thiomaltol complex has been characterized by both X-ray crystallography and X-ray spectroscopy. In addition, the steric restrictions of the active site force the ligands into a ‘flattened’ mode of coordination compared with inorganic model complexes. This change in geometry has been shown by density functional computations to significantly decrease the strength of the metal-ligand binding. Collectively, these data demonstrate that the mode of binding by small metal-binding groups (MBGs) can be significantly influenced by the protein active site. Diminishing the strength of the metal-ligand bond results in unconventional modes of metal coordination not found in typical coordination compounds or even carefully engineered active site models, and understanding these effects is critical to the rational design of inhibitors that target clinically relevant metalloproteins.

show abstract

Section: Introductionmentioning

confidence: 99%

‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site

Martin

Blachly²,

Marts

et al. 2014

J. Am. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…According to ZBG studies, using the coordinates of protein-ligand complex structures obtained from the PDB, the most frequently found ZBG is carboxylate, followed by sulfonamide, hydroxamate, and phosphonate/phosphate. Whereas carboxylates bound to the zinc via both monodentate and bidentate interactions, the hydroxamates bound dominantly in a bidentate manner [19]. The median distances from the nitrogen, oxygen, and sulfur atoms were 1.99, 2.05, and 2.28 Å respectively.…”

Section: Docking Studies On Mmp-9mentioning

confidence: 93%

“…The reaction mixture was then cooled to room temperature and the solid precipitated was filtered off and washed with toluene (or filtered, after the mixture was concentrated in vacuo (19), and then taken up with an aqueous solution of 10 % Na 2 CO 3 and washed with water, as for 18). The crude product was then purified by flash chromatography and recrystallized or directly recrystallized.…”

Section: 3-thiazolidin-3-yl)propanamides 13-19mentioning

confidence: 99%

4-Thiazolidinone Derivatives as MMP Inhibitors in Tissue Damage: Synthesis, Biological Evaluation and Docking Studies

Incerti

Crascì

Vicini

et al. 2017

Preprint

View full text Add to dashboard Cite

Nine 2-(1,2-benzothiazol-3-yl)-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl) propanamides were designed and synthesized, combining benzisothiazole and 4-thiazolidinone in one frame. The aim of the study was to verify their effectiveness to contrast the inflammatory/oxidative process in which free oxygen and nitrite (ROS and RNS) radicals, advanced glycation products (AGEs), inflammatory cytokines and matrix metalloproteinases (MMPs) are involved. Docking studies of all the compounds were performed in order to explore their binding mode at the MMP-9 protein. An appreciable anti-inflammatory/wound healing effects of the tested compounds was highlighted.Derivative 23, bearing a 4-carboxyphenyl substituent at C2 of the 4-thiazolidinone ring, exhibited the highest activity, being able to inhibit MMP-9 at nanomolar level (IC 50 = 40 nM).

show abstract

“…Zn 2+ is believed to be one of the most potent inhibitor of proton channels. The inhibitory action of Zn 2+ is derived from the metal ion binding to histidine residues, and also to the thiol group of the cysteine residues (43). In fact, it has been reported that Zn 2+ does not inhibit NADH oxidation at the flavin site or intramolecular electron transfer in complex I, but it does inhibit proton transfer to bound quinone or proton translocation (25).…”

Section: +mentioning

confidence: 99%

Roles of subunit NuoL in the proton pumping coupling mechanism of NADH:ubiquinone oxidoreductase (complex I) fromEscherichia coli

et al. 2016

View full text Add to dashboard Cite

Respiratory complex I has an L-shaped structure formed by the hydrophilic arm responsible for electron transfer and the membrane arm that contains protons pumping machinery. Here, to gain mechanistic insights into the role of subunit NuoL, we investigated the effects of Mg 2+ , Zn 2+ and the Na + /H + antiporter inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on proton pumping activities of various isolated NuoL mutant complex I after reconstitution into Escherichia coli double knockout (DKO) membrane vesicles lacking complex I and the NADH dehydrogenase type 2. We found that Mg 2+ was critical for proton pumping activity of complex I. At 2 mM Zn 2+ , proton pumping of the wild-type was selectively inhibited without affecting electron transfer; no inhibition in proton pumping of D178N and D400A was observed, suggesting the involvement of these residues in Zn 2+ binding. Fifteen micromolar of EIPA caused up to $40% decrease in the proton pumping activity of the wild-type, D303A and D400A/E, whereas no significant change was detected in D178N, indicating its possible involvement in the EIPA binding. Furthermore, when menaquinone-rich DKO membranes were used, the proton pumping efficiency in the wild-type was decreased significantly ($50%) compared with NuoL mutants strongly suggesting that NuoL is involved in the high efficiency pumping mechanism in complex I.

show abstract

Metal–ligand interactions: An analysis of zinc binding groups using the Protein Data Bank

Cited by 41 publications

References 15 publications

‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site

‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site

4-Thiazolidinone Derivatives as MMP Inhibitors in Tissue Damage: Synthesis, Biological Evaluation and Docking Studies

Roles of subunit NuoL in the proton pumping coupling mechanism of NADH:ubiquinone oxidoreductase (complex I) fromEscherichia coli

Contact Info

Product

Resources

About