Surveys of X-ray structures of Ca2+-containing and lanthanide ion-containin
g proteins and coordination complexes have been performed and structural fe
atures of the metal binding sites compared. A total of 515 structures of Ca
2+-containing proteins were considered, although the final data set contain
ed only 44 structures and 60 Ca2+ binding sites with a total of 323 ligands
. Eighteen protein structures containing lanthanide ions were considered wi
th a final data set containing eight structures and 11 metal binding sites.
Structural features analysed include coordination numbers of the metal ion
s, the identity of their ligands, the denticity of carboxylate ligands, and
the type of secondary structure from which the ligands are derived. Three
general types of calcium binding site were identified in the final data set
: class I sites supply the Ca2+ ligands from a continuous short sequence of
amino acids; class II sites have one ligand supplied by a part of the amin
o acid sequence far removed from the main binding sequence; and class III s
ites are created by amino acids remote from one another in the sequence. Th
e abundant EF-hand type of Ca2+ binding site was under-represented in the d
ata set of structures analysed as far as its biological distribution is con
cerned, but was adequately represented for the chemical survey undertaken.
A turn or loop structure was found to provide the bulk of the ligands to Ca
2+, but helix and sheet secondary structures are slightly better providers
of bidentate carboxylate ligation than turn or loop structures. The average
coordination number for Ca2+ was 6.0, though for EF-hand sites it is 7. Th
e average coordination number, of a lanthanide ion in an intrinsic protein
Ca2+ site was 7.2, but for the adventitious sites was only 4.4. A survey of
the Cambridge Structural Database showed there are small-molecule lanthani
de complexes with low coordination numbers but it is likely that water mole
cules, which do not appear in the electron density maps, are present for so
me lanthanide sites in proteins. A detailed comparison of the well-defined
Ca2+ and lanthanide ion binding sites suggests that a reduction of hydrogen
bonding associated with the ligating residues of the binding sites contain
ing lanthanide ions may be a response to the additional positive charge of
the lanthanide ion. Major structural differences between Ca2+ binding sites
with weak and strong binding affinities were not obvious, a consequence of
long-range electrostatic interactions and metal ion-induced protein confor
mational changes modulating affinities.