Zinc's exclusive tetrahedral coordination governed by its electronic structure

Zinc is a critical component of more than 300 proteins including farnesyltr ansferase, matrix metalloproteinases and endostatin that are involved in th e front-line cancer research, and a host of proteins termed zinc fingers th at mediate protein-protein and protein-nucleic acid interactions. Despite t he growing appreciation of zinc in modern biology, the knowledge of zinc's coordination nature in proteins remains controversial. It is typically assu med that Zn2+ coordinates to four to six ligands, which led to intensive de bates about whether the catalysis of some zinc proteins is regulated by zin c's four- or five-coordinate complex. Here we report the inherent uncertain ty, due to the experimental resolution, in classifying zinc's five- and six -coordinate complexes in protein crystal structures, and put forward a tetr ahedral coordination concept that Zn2+ coordinates to only four ligands mai nly because of its electronic structure that accommodates four pairs of ele ctrons in its vacant 4s4p(3) orbitals. Experimental observations of five- a nd six-coordinate complexes were due to one or two pairs of ambidentate coo rdinates that exchanged over time and were averaged as bidentate coordinate s. This concept advances understanding of zinc's coordination nature in pro teins and the means to study zinc proteins to unlock the secrets of Zn2+ in human biology. In particular, according to this concept, it is questionabl e to study zinc's coordination in proteins with Co2+ as a surrogate of Zn2 for spectroscopic measurements, since the former is a d(7) unclosed shell divalent cation whereas the latter is a d(10) closed shell divalent cation.