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

[Image: see text] 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)...

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Autores principales: Martin, David P., Blachly, Patrick G., Marts, Amy R., Woodruff, Tessa M., de Oliveira, César A. F., McCammon, J. Andrew, Tierney, David L., Cohen, Seth M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104174/
https://www.ncbi.nlm.nih.gov/pubmed/24635441
http://dx.doi.org/10.1021/ja500616m
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author Martin, David P.
Blachly, Patrick G.
Marts, Amy R.
Woodruff, Tessa M.
de Oliveira, César A. F.
McCammon, J. Andrew
Tierney, David L.
Cohen, Seth M.
author_facet Martin, David P.
Blachly, Patrick G.
Marts, Amy R.
Woodruff, Tessa M.
de Oliveira, César A. F.
McCammon, J. Andrew
Tierney, David L.
Cohen, Seth M.
author_sort Martin, David P.
collection PubMed
description [Image: see text] 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 Zn(2+) 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 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.
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spelling pubmed-41041742015-03-17 ‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site Martin, David P. Blachly, Patrick G. Marts, Amy R. Woodruff, Tessa M. de Oliveira, César A. F. McCammon, J. Andrew Tierney, David L. Cohen, Seth M. J Am Chem Soc [Image: see text] 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 Zn(2+) 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 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. American Chemical Society 2014-03-17 2014-04-09 /pmc/articles/PMC4104174/ /pubmed/24635441 http://dx.doi.org/10.1021/ja500616m Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Martin, David P.
Blachly, Patrick G.
Marts, Amy R.
Woodruff, Tessa M.
de Oliveira, César A. F.
McCammon, J. Andrew
Tierney, David L.
Cohen, Seth M.
‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site
title ‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site
title_full ‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site
title_fullStr ‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site
title_full_unstemmed ‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site
title_short ‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site
title_sort ‘unconventional’ coordination chemistry by metal chelating fragments in a metalloprotein active site
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104174/
https://www.ncbi.nlm.nih.gov/pubmed/24635441
http://dx.doi.org/10.1021/ja500616m
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