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PDBsum entry 1dql
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Immune system
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PDB id
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1dql
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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An unusual human igm antibody with a protruding hcdr3 and high avidity for its peptide ligands.
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Authors
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P.A.Ramsland,
L.Shan,
C.R.Moomaw,
C.A.Slaughter,
Z.Fan,
L.W.Guddat,
A.B.Edmundson.
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Ref.
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Mol Immunol, 2000,
37,
295-310.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the Fv molecule from a human monoclonal IgM
cryoglobulin (Mez) was determined at 2.6 A resolution. Amino acid sequences of
framework regions (FR) of the Mez light (L) and heavy (H) chain variable domains
(VL and VH) are highly similar to their counterparts in another human Fv (Pot)
previously subjected to X-ray analysis in our laboratory. As expected, the
three-dimensional (3-D) structures of FR are quite similar in the two proteins,
as are four of the six complementarity-determining regions (CDRs): CDRs 1 and 2
for both L and H chains. Absence of Pro 95L from the LCDR3 loop in Mez VL
(relative to Pot LCDR3) results in compression of this loop and creates more
space in the VL-VH interface. In the two IgMs, HCDR3 conformations differ
significantly from all previously defined conformations for these loops. Pot has
a 12-residue HCDR3 that collapses to fill all available space in the VL-VH
domain interface, resulting in the formation of a relatively flat platform for
antigen binding. In Mez, the HCDR3 is two residues longer and is comprehensively
different. A semi-rigid ascending segment dominated by a Pro-Pro-Tyr sequence
protrudes out into solvent. The descending portion has the sequence
Gly-Trp-Gly-Gly-Gly, which promotes high local flexibility. This segment folds
across the VL-VH domain interface to interact with residues in LCDR3. These
features partition the Mez active site into two compartments, a large cavity
between VL and VH and a smaller cavity lined entirely by constituents of the
three heavy chain CDRs. Such an unusual topographical feature indicates why the
Mez IgM does not bind to the Fc portion of intact human IgG antibodies in
immunoassays yet interacts with high avidity with many Fc-derived octapeptides.
The cavities are expected to be the repositories for the Fc-derived peptides,
while the semi-rigid protrusion of the Mez HCDR3 prevents the close approach of
another macromolecule (e.g. intact IgG) to the active site.
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