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PDBsum entry 3ch2
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References listed in PDB file
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Key reference
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Title
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Structural insights into the protease-Like antigen plasmodium falciparum sera5 and its noncanonical active-Site serine.
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Authors
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A.N.Hodder,
R.L.Malby,
O.B.Clarke,
W.D.Fairlie,
P.M.Colman,
B.S.Crabb,
B.J.Smith.
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Ref.
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J Mol Biol, 2009,
392,
154-165.
[DOI no: ]
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PubMed id
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Abstract
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The sera genes of the malaria-causing parasite Plasmodium encode a family of
unique proteins that are maximally expressed at the time of egress of parasites
from infected red blood cells. These multi-domain proteins are unique,
containing a central papain-like cysteine-protease fragment enclosed between the
disulfide-linked N- and C-terminal domains. However, the central fragment of
several members of this family, including serine repeat antigen 5 (SERA5),
contains a serine (S596) in place of the active-site cysteine. Here we report
the crystal structure of the central protease-like domain of Plasmodium
falciparum SERA5, revealing a number of anomalies in addition to the putative
nucleophilic serine: (1) the structure of the putative active site is not
conducive to binding substrate in the canonical cysteine-protease manner; (2)
the side chain of D594 restricts access of substrate to the putative active
site; and (3) the S(2) specificity pocket is occupied by the side chain of Y735,
reducing this site to a small depression on the protein surface. Attempts to
determine the structure in complex with known inhibitors were not successful.
Thus, despite having revealed its structure, the function of the catalytic
domain of SERA5 remains an enigma.
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Figure 1.
Fig. 1. Sequence alignment of cathepsin L and SERA5E. (a)
Structural alignment^29 of SERA5E with the enzyme domain of
cathepsin L (CatL; PDB 1mhw). Secondary-structure elements
(helices and strands, cylinders and arrows, respectively) in
SERA5E are indicated. Lowercase font refers to structurally
unaligned regions. (b) Secondary-structure topology of SERA5E,
showing disulfide bonding between cysteine residues; disulfide
bonds unique to SERA5E are asterisked (1–2* between C567 and
C572, 3–5* between C581 and C610). Black circles indicate the
relative disposition of the triad of catalytic residues S596,
H762, and N787.
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Figure 2.
Fig. 2. Structural comparison of SERA5E and cathepsin L. (a)
Cartoon diagram of SERA5E. The N-terminal domain is to the left
and the C-terminal domain to the right of the central catalytic
cleft. The side-chain atoms of the catalytic triad, S596, H762,
and N787, are shown along with those from residues that line the
substrate-binding cleft, Q590, D594, D637, E638, S641, M643,
K701, Y703, A705, E707, R710, Y735, S816, and V818. The residues
connecting N691 to D699 in SERA5E are disordered in structures 1
and 2. (b) Cartoon diagram of cathepsin L. The side-chain atoms
of the catalytic triad in cathepsin L, C25, H163, and N187 are
highlighted, along with the side-chain atoms of A135, composing
the S[2] pocket. (c) Structural comparison of the
substrate-binding sites. The peptide backbone atoms of SERA5E
G639–S641 and cathepsin L G67–L69 are shown. The peptide
plane of G639 in structure 1 and structure 2 of SERA5E is
rotated  vert,
similar 90° compared to the orientation of the equivalent
residue in cathepsin L, whereas in structure 3, there is a
rotation of vert,
similar 45° of this and the proceeding peptide plane (S640).
The loop in the N-terminal domain leading to the strand
responsible for orienting substrates [C627–G639 and C56–G67
in SERA5E (tan) and cathepsin L (cyan), respectively] is
highlighted—this loop adopts a different path in SERA5E
compared to that in cathepsin L. The disulfide bond at the
C-terminal end of this loop is indicated. The side chains of the
catalytic-triad residues in SERA5E (S596, H762, N787) are found
in identical orientations and positions in cathepsin L (C25,
H163, N187). The S[2] pocket in cathepsin L, formed in part by
A135, is occupied by Y735 in SERA5E.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2009,
392,
154-165)
copyright 2009.
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