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PDBsum entry 4kkd
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References listed in PDB file
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Key reference
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Title
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The X-Ray crystal structure of mannose-Binding lectin-Associated serine proteinase-3 reveals the structural basis for enzyme inactivity associated with the carnevale, Mingarelli, Malpuech, And michels (3mc) syndrome.
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Authors
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T.Yongqing,
P.G.Wilmann,
S.B.Reeve,
T.H.Coetzer,
A.I.Smith,
J.C.Whisstock,
R.N.Pike,
L.C.Wijeyewickrema.
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Ref.
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J Biol Chem, 2013,
288,
22399-22407.
[DOI no: ]
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PubMed id
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Abstract
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The mannose-binding lectin associated-protease-3 (MASP-3) is a member of the
lectin pathway of the complement system, a key component of human innate and
active immunity. Mutations in MASP-3 have recently been found to be associated
with Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome, a severe
developmental disorder manifested by cleft palate, intellectual disability, and
skeletal abnormalities. However, the molecular basis for MASP-3 function remains
to be understood. Here we characterize the substrate specificity of MASP-3 by
screening against a combinatorial peptide substrate library. Through this
approach, we successfully identified a peptide substrate that was 20-fold more
efficiently cleaved than any other identified to date. Furthermore, we
demonstrated that mutant forms of the enzyme associated with 3MC syndrome were
completely inactive against this substrate. To address the structural basis for
this defect, we determined the 2.6-Å structure of the zymogen form of the
G666E mutant of MASP-3. These data reveal that the mutation disrupts the active
site and perturbs the position of the catalytic serine residue. Together, these
insights into the function of MASP-3 reveal how a mutation in this enzyme causes
it to be inactive and thus contribute to the 3MC syndrome.
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