In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 20 ( 1999-09-28), p. 10968-10975
Abstract:
The three-dimensional structures of the inactive protein precursors
(zymogens) of the serine, cysteine, aspartic, and metalloprotease classes of proteolytic enzymes are known.
Comparisons of these structures with those of the mature, active proteases reveal that, in general, the preformed, active conformations
of the residues involved in catalysis are rendered sterically inaccessible to substrates by the residues of the zymogens’ N-terminal
extensions or prosegments. The prosegments interact in nonsubstrate-like fashions with the residues of the active sites in
most of the cases. The gastric aspartic proteases have a well-characterized zymogen conversion pathway. Structures of human
progastricsin, the inactive intermediate 2, and active human pepsin are known and have been used to define the conversion pathway. The
structure of the zymogen precursor of plasmepsin II, the malarial aspartic protease, shows a new twist on the mode of inactivation used
by the gastric zymogens. The prosegment of proplasmepsin disrupts the active conformation of the two catalytic aspartic acid residues by
inducing a major reorientation of the two domains of the mature protease. The picornaviral 2A and 3C proteases have a
chymotrypsin-like tertiary structure but with a cysteine nucleophile. These enzymes cleave themselves from the viral polyprotein
in cis (intramolecular cleavage) and carry out trans cleavages of other scissile peptides important for the virus life cycle. Although the
structure of the precursor viral polyprotein is unknown, it probably resembles the organization of the proenzymes of the bacterial serine
proteases, subtilisin, and α-lytic protease. Cleavage of the prosegment is known to occur in cis for these precursor molecules.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.96.20.10968
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1999
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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