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PDBsum entry 1pg7
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Immune system
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PDB id
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1pg7
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Contents |
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213 a.a.
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213 a.a.
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210 a.a.
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220 a.a.
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* Residue conservation analysis
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PDB id:
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| Name: |
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Immune system
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Title:
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Murine 6a6 fab in complex with humanized anti-tissue factor d3h44 fab
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Structure:
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Humanized antibody d3h44. Chain: h, i. Fragment: antigen-binding fragment. Engineered: yes. Humanized antibody d3h44. Chain: l, m. Fragment: antigen-binding fragment. Engineered: yes. Murine antibody 6a6 fab fragment.
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Source:
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Mus musculus, homo sapiens. Organism_taxid: 10090, 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. House mouse. Organism_taxid: 10090. Organism_taxid: 10090
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Biol. unit:
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Tetramer (from
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Resolution:
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2.50Å
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R-factor:
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0.217
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R-free:
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0.265
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Authors:
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C.Eigenbrot,Y.G.Meng,R.Krishnamurthy,M.T.Lipari,L.Presta,B.Devaux, T.Wong,P.Moran,S.Bullens,D.Kirchhofer
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Key ref:
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C.Eigenbrot
et al.
(2003).
Structural insight into how an anti-idiotypic antibody against D3H44 (anti-tissue factor antibody) restores normal coagulation.
J Mol Biol,
331,
433-446.
PubMed id:
DOI:
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Date:
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27-May-03
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Release date:
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26-Aug-03
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PROCHECK
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Headers
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References
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P01857
(IGHG1_HUMAN) -
Immunoglobulin heavy constant gamma 1 from Homo sapiens
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Seq:
Struc:
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399 a.a.
213 a.a.
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Q7Z3Y4
(Q7Z3Y4_HUMAN) -
Ig-like domain-containing protein from Homo sapiens
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Seq:
Struc:
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236 a.a.
213 a.a.*
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DOI no:
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J Mol Biol
331:433-446
(2003)
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PubMed id:
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Structural insight into how an anti-idiotypic antibody against D3H44 (anti-tissue factor antibody) restores normal coagulation.
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C.Eigenbrot,
Y.G.Meng,
R.Krishnamurthy,
M.T.Lipari,
L.Presta,
B.Devaux,
T.Wong,
P.Moran,
S.Bullens,
D.Kirchhofer.
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ABSTRACT
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6A6 is a murine monoclonal antibody raised against the humanized anti-tissue
factor antibody D3H44. 6A6 is able to completely neutralize the anticoagulant
activity of D3H44 in tissue factor-dependent functional assays, such as
endotoxin-induced whole blood clotting, prothrombin time, as well as factor X
and factor IX activation. ELISA-type assays further showed that 6A6 binds to an
epitope with critical determinants on the V(L) domain of D3H44. The possibility
that the anti-idiotypic 6A6 might carry an "internal image" of the
original antigen (tissue factor) was examined using the X-ray structure of the
6A6-Fab/D3H44-Fab complex determined at 2.5A resolution. We find that 6A6
structurally mimics tissue factor only so far as it combines with the antigen
recognition surface of D3H44. While 6A6 contacts both V(L) and V(H) domains of
D3H44, as does tissue factor, there is more contact with the D3H44 V(L) domain
and less with the D3H44 V(H) domain relative to the tissue factor contacts on
D3H44. Additionally, there is an almost total lack of correspondence between 6A6
and tissue factor at the level of amino acid side-chain functional groups.
Despite the fact that both tissue factor and 6A6 are composed largely of
beta-sheets, they present fundamentally different elements of secondary
structure to D3H44; tissue factor presents beta-sheets edge-on, while 6A6 uses
mostly loops. Finally, the finding that 6A6 competes with tissue factor for
D3H44 binding raises the possibility of using 6A6 as an antidote for D3H44
anticoagulant therapy. To this end, we constructed a chimeric murine/human
6A6-Fab, which effectively neutralized D3H44 and fully restored tissue factor
function in enzymatic assays.
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Selected figure(s)
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Figure 4.
Figure 4. Representative electron density from the
6A6-Fab/D3H44-Fab crystal structure. Shown is a section of
CDR-H1 of 6A6-Fab from the final model with 2F[o] -F[c] density
contoured at 1.0 rmsd.
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Figure 9.
Figure 9. Orientation of b-sheets from 6A6-Fab (green) and
TF (pink) with respect to D3H44-Fab (grey surface).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2003,
331,
433-446)
copyright 2003.
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Figures were
selected
by the author.
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