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

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 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.