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PDBsum entry 3cvp
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Transport protein
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PDB id
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3cvp
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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 recognition of peroxisomal targeting signal 1 by trypanosoma brucei peroxin 5.
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Authors
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P.Sampathkumar,
C.Roach,
P.A.Michels,
W.G.Hol.
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Ref.
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J Mol Biol, 2008,
381,
867-880.
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PubMed id
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Abstract
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Glycosomes are peroxisome-like organelles essential for trypanosomatid
parasites. Glycosome biogenesis is mediated by proteins called "peroxins," which
are considered to be promising drug targets in pathogenic Trypanosomatidae. The
first step during protein translocation across the glycosomal membrane of
peroxisomal targeting signal 1 (PTS1)-harboring proteins is signal recognition
by the cytosolic receptor peroxin 5 (PEX5). The C-terminal PTS1 motifs interact
with the PTS1 binding domain (P1BD) of PEX5, which is made up of seven
tetratricopeptide repeats. Obtaining diffraction-quality crystals of the P1BD of
Trypanosoma brucei PEX5 (TbPEX5) required surface entropy reduction mutagenesis.
Each of the seven tetratricopeptide repeats appears to have a residue in the
alpha(L) conformation in the loop connecting helices A and B. Five crystal
structures of the P1BD of TbPEX5 were determined, each in complex with a hepta-
or decapeptide corresponding to a natural or nonnatural PTS1 sequence. The PTS1
peptides are bound between the two subdomains of the P1BD. These structures
indicate precise recognition of the C-terminal Leu of the PTS1 motif and
important interactions between the PTS1 peptide main chain and up to five
invariant Asn side chains of PEX5. The TbPEX5 structures reported here reveal a
unique hydrophobic pocket in the subdomain interface that might be explored to
obtain compounds that prevent relative motions of the subdomains and interfere
selectively with PTS1 motif binding or release in trypanosomatids, and would
therefore disrupt glycosome biogenesis and prevent parasite growth.
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