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Abstract
The three-dimensional structure of the enzyme myeloperoxidase has been determined
by X-ray crystallography to 3 A resolution. Two heavy atom derivatives were used to
phase an initial multiple isomorphous replacement map that was subsequently improved
by solvent flattening and non-crystallographic symmetry averaging. Crystallographic
refinement gave a final model with an R-factor of 0.257. The root-mean-square deviations
from ideality for bond lengths and angles were 0.011 A and 3.8 degrees. Two, apparently
identical, halves of the molecule are related by local dyad and covalently linked
by a single disulfide bridge. Each half-molecule consists of two polypeptide chains
of 108 and 466 amino acid residues, a heme prosthetic group, a bound calcium ion and
at least three sites of asparagine-linked glycosylation. There are six additional
intra-chain disulfide bonds, five in the large polypeptide and one in the small. A
central core region that includes the heme binding site is composed of five alpha-helices.
Regions of the larger polypeptide surrounding this core are organized into locally
folded domains in which the secondary structure is predominantly alpha-helical with
very little organized beta-sheet. A proximal ligand to the heme iron atom has been
identified as histidine 336, which is in turn hydrogen-bonded to asparagine 421. On
the distal side of the heme, histidine 95 and arginine 239 are likely to participate
directly in the catalytic mechanism, in a manner analogous to the distal histidine
and arginine of the non-homologous enzyme cytochrome c peroxidase. The site of the
covalent linkage to the heme has been tentatively identified as glutamate 242, although
the chemical nature of the link remains uncertain. The calcium binding site has been
located in a loop comprising residues 168 to 174 together with aspartate 96. Myeloperoxidase
is a member of a family of homologous mammalian peroxidases that includes thyroid
peroxidase, eosinophil peroxidase and lactoperoxidase. The heme environment, defined
by our model for myeloperoxidase, appears to be highly conserved in these four mammalian
peroxidases. Furthermore, the conservation of all 12 cysteine residues involved in
the six intra-chain disulfide bonds and the calcium binding loop suggests that the
three-dimensional structures of members of this gene family are likely to be quite
similar.