Abstract:
:The X-ray crystal structure of a salicylhydroxamic acid (SHA) inhibitory complex with human myeloperoxidase (MPO) has been determined at 2.3 A resolution. The aromatic ring of the inhibitor binds to a hydrophobic region at the entrance to the distal heme pocket between heme pyrrole ring D and the side chain of Arg 239. The hydroxamic acid moiety is hydrogen bonded to both the distal histidine 95 and the adjacent glutamine 91 amide group but is not coordinated to the heme iron. SHA binding displaces three water molecules from the distal heme cavity and causes a small shift in the position of a fourth water molecule. Otherwise, there are no significant conformational differences between the active site regions of the complex and the native enzyme. The ability of the three SHA oxygen atoms to closely duplicate the hydrogen-bonding pattern of these three water molecules in the native enzyme is postulated to account for the strong binding of this inhibitor to MPO. The mode of binding of SHA to MPO provides information on the binding sites for aromatic peracid substrates that promote compound I formation as well as aromatic alcohols and amines that carry out single-electron reductions of compound I. Similarities in the hydrogen-bonding patterns of amino acid residues and water molecules in the distal heme pockets of myeloperoxidase and the nonhomologous cytochrome c peroxidase suggest that they may have similar mechanisms of compound I formation. A model is presented for a prereaction complex of myeloperoxidase in which hydrogen peroxide is hydrogen bonded to the distal histidine, as a prerequisite for deprotonation and subsequent binding at the sixth coordination site of the heme iron.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Davey CA,Fenna REdoi
10.1021/bi960577msubject
Has Abstractpub_date
1996-08-20 00:00:00pages
10967-73issue
33eissn
0006-2960issn
1520-4995pii
bi960577mjournal_volume
35pub_type
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