‘Unconventional’ Coordination Chemistry by Metal Chelating Fragments in a Metalloprotein Active Site
酵素中とモデル錯体では、同じリガンドでもバインドの角度が違うということを論文にしている。なんで？という所の考察とか、ここからなにができるの？というのは正直弱いとおもうけど、着眼点はファインだと思います。こういう配位角や距離が、最も安定な位置関係からずれる事による現象は、個人的には非常に興味深いです。
イントロに、"The results not only show the utility but also the limitations of bioinorganic modeling while highlighting the subtle influence of active site structure on metal–ligand bonding. Such subtle effects on coordination chemistry are not readily predicted by current paradigms in bioinorganic chemistry and, consequently, are not implemented in standard drug design efforts directed at metalloproteins."
と、ありますが、この辺りは伊東研としても切り込めるところではないでしょうか。
Article
David P. Martin †, Patrick G. Blachly †, Amy R. Marts‡, Tessa M. Woodruff ‡, César A. F. de Oliveira 
, J. Andrew McCammon †§, David L. Tierney *‡, andSeth M. Cohen *†
, J. Andrew McCammon †§, David L. Tierney *‡, andSeth M. Cohen *†
†Department of Chemistry and Biochemistry,§Pharmacology, and Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California 92093, United States
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California 92093, United States
‡ Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
J. Am. Chem. Soc., Article ASAP
DOI: 10.1021/ja500616m
Publication Date (Web): March 17, 2014
Copyright © 2014 American Chemical Society
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 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.
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