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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 \u2018flattened\u2019 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\u2013ligand 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\u2013ligand 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.<\/jats:p>","DOI":"10.1021\/ja500616m","type":"journal-article","created":{"date-parts":[[2014,3,17]],"date-time":"2014-03-17T12:55:40Z","timestamp":1395060940000},"page":"5400-5406","source":"Crossref","is-referenced-by-count":22,"title":["\u2018Unconventional\u2019\nCoordination Chemistry by\nMetal Chelating Fragments in\na Metalloprotein Active Site"],"prefix":"10.1021","volume":"136","author":[{"given":"David P.","family":"Martin","sequence":"first","affiliation":[{"name":"University of California, San Diego , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick G.","family":"Blachly","sequence":"additional","affiliation":[{"name":"University of California, San Diego , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy R.","family":"Marts","sequence":"additional","affiliation":[{"name":"Miami University , , , ,","place":["Oxford, Ohio, United States, 45056"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa M.","family":"Woodruff","sequence":"additional","affiliation":[{"name":"Miami University , , , ,","place":["Oxford, Ohio, United States, 45056"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ce\u0301sar A. 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