Structural comparison of sulfodiimine and sulfonamide inhibitors in their complexes with zinc enzymes.
The three-dimensional structure of (L(-)-2-carboxy-3-phenylpropyl) methylsulfodiimine in its complex with the zinc metalloenzyme carboxypeptidase A has been determined at 2.25-A resolution by x-ray crystallographic methods. This is the first example of a sulfodiimine-containing inhibitor binding to a zinc enzyme, and the structure of the enzyme-inhibitor complex reveals that the tetrahedral sulfodiimine group coordinates to the active site zinc ion in unidentate fashion. The zinc-coordinated nitrogen atom of the sulfodiimine group is also within hydrogen bonding distance to active site base Glu-270; presumably, the sulfodiimine is ionized and accepts a hydrogen bond from protonated Glu-270. The other sulfodiimine nitrogen accepts a hydrogen bond from Arg-127, and the inhibitor binds as a possible analogue of the tetrahedral transition state (or intermediate) in a promoted water pathway for peptide hydrolysis. The unidentate sulfodiimine-zinc binding mode observed in this enzyme-inhibitor complex is reminiscent of that observed in sulfonamide complexes with the zinc metalloenzyme carbonic anhydrase II, and the structural features of sulfodiimine- and sulfonamide-zinc interactions exhibit important similarities among recently determined structures of enzyme-inhibitor complexes: ionized nitrogens bind to zinc in each structure, and these nitrogens are engaged in hydrogen bond interactions with neighboring enzyme residues.
Cappalonga
A M
AM
Department of Chemistry, University of Pennsylvania, Philadelphia 19104-6323.
Alexander
R S
RS
Christianson
D W
DW
D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D043422:Carboxypeptidases A; D003461:Crystallography; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005583:Fourier Analysis; D007097:Imines / Q000737:chemistry* / Q000494:pharmacology; D008667:Metalloproteins / Q000737:chemistry; D011487:Protein Conformation; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014961:X-Ray Diffraction; D015032:Zinc
D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D007097:Imines; D008667:Metalloproteins; D013440:Sulfides; D013449:Sulfonamides; C076812:(2-carboxy-3-phenylpropyl)methylsulfodiimide; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D015032:Zinc