Predicted structures of the cGMP binding domains of the cGMP-dependent protein kinase: a key alanine/threonine difference in evolutionary divergence of cAMP and cGMP binding sites.
Mammalian cGMP- and cAMP-dependent protein kinase show considerable similarity in amino acid sequence, although they specifically bind different cyclic nucleotides. Results of cGMP analogue binding experiments, combined with modeling of the cGMP binding sites by analogy to the structure of the homologous catabolite gene activator protein, suggest that a threonine residue forms a hydrogen bond with the 2-NH2 of cGMP. This threonine is invariant in all cGMP binding domains, but the corresponding residue in 23 out of 24 cAMP binding sites of protein kinases is alanine, which cannot form the same hydrogen bond. This alanine/threonine difference has the potential for discriminating between cAMP and cGMP and may be important in the evolutionary divergence of cyclic nucleotide binding sites.
Weber
I T
IT
Crystallography Laboratory, NCI-Frederick Cancer Research Facility, Maryland 21701.
Shabb
J B
JB
Corbin
J D
JD
D000409:Alanine; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005075:Biological Evolution; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011494:Protein Kinases / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D013912:Threonine
D013912:Threonine; D000242:Cyclic AMP; D011494:Protein Kinases; D006152:Cyclic GMP; D000409:Alanine