4MLX

Structure of a bidentate 3-hydroxy-4H-pyran-4-thione ligand bound to hCAII

Summary for 4MLX

• Entry DOI: 10.2210/pdb4mlx/pdb
• Related: 4MLT
• Descriptor: Carbonic anhydrase 2, ZINC ION, MERCURIBENZOIC ACID, ... (6 entities in total)
• Functional Keywords: lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 29896.48

Authors

Martin, D.P.,Cohen, S.M. (deposition date: 2013-09-06, release date: 2014-07-02, Last modification date: 2023-09-20)

Primary citation

Martin, D.P.,Blachly, P.G.,Marts, A.R.,Woodruff, T.M.,de Oliveira, C.A.,McCammon, J.A.,Tierney, D.L.,Cohen, S.M.
'Unconventional' coordination chemistry by metal chelating fragments in a metalloprotein active site.
J.Am.Chem.Soc., 136:5400-5406, 2014

PubMed Abstract: 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.

PubMed: 24635441
DOI: 10.1021/ja500616m

Experimental method

X-RAY DIFFRACTION (1.65 Å)