Physical basis of structural and catalytic Zn-binding sites in proteins.
Zn(2+), an element that is essential to all life forms, can play a catalytic or a solely structural role. Previous works have shown that Zn(2+) binds preferentially to water molecules and His in catalytic sites, but to Cys(-) instructural sites, but the molecular basis for the observed ligand preference is unclear. Here, we show that the different Zn(2+) roles are also reflected in the different bond distances to Zn(2+) in structural and catalytic sites. We reveal the physical basis for the observed differences between structural and catalytic Zn sites: In most catalytic sites, water is found bound to Zn(2+) as it transfers the least charge to Zn(2+) and is less bulky compared to the protein ligands, enabling Zn(2+) to serve as a Lewis acid in catalysis. In most structural sites, however, >/= 2 Cys(-) are found bound to Zn(2+), as Cys(-) transfers the most charge to Zn(2+) and reduces the Zn charge to such an extent that Zn(2+) can no longer act as a Lewis acid; furthermore, steric repulsion among the bulky Cys(S(-)) prevents Zn(2+) from accommodating another ligand. Based on the observed ligand preference and Zn-ligand distance differences between structural and catalytic Zn sites, we present a simple method for distinguishing the two types of sites and for verifying the catalytic role of Zn(2+). Finally, we discuss how the physical bases revealed aid in designing potential drug molecules that target Zn proteins.
Lee
Yu-Ming
YM
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Lim
Carmay
C
D001665:Binding Sites; D020134:Catalytic Domain; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000378:metabolism*
D008024:Ligands; D011506:Proteins; D014867:Water; D015032:Zinc; D003545:Cysteine