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PDBsum entry 3ffd
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Immune system/hormone
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PDB id
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3ffd
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Contents |
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210 a.a.
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217 a.a.
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18 a.a.
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* Residue conservation analysis
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PDB id:
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Immune system/hormone
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Title:
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Structure of parathyroid hormone-related protein complexed to a neutralizing monoclonal antibody
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Structure:
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Monoclonal antibody, heavy chain, fab fragment. Chain: a. Engineered: yes. Monoclonal antibody, light chain, fab fragment. Chain: b. Engineered: yes. Parathyroid hormone-related protein. Chain: p. Synonym: pth-rp, pthrp.
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Source:
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Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: mus musculus. Expression_system_taxid: 10090. Expression_system_cell: hybridoma cell. Homo sapiens. Human. Organism_taxid: 9606.
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Resolution:
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2.00Å
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R-factor:
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0.224
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R-free:
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0.271
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Authors:
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W.J.Mckinstry,G.Polekhina,H.Diefenbach-Jagger,P.W.M.Ho,K.Sato, E.Onuma,M.T.Gillespie,T.J.Martin,M.W.Parker
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Key ref:
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W.J.McKinstry
et al.
(2009).
Structural basis for antibody discrimination between two hormones that recognize the parathyroid hormone receptor.
J Biol Chem,
284,
15557-15563.
PubMed id:
DOI:
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Date:
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03-Dec-08
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Release date:
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28-Apr-09
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PROCHECK
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Headers
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References
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No UniProt id for this chain
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DOI no:
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J Biol Chem
284:15557-15563
(2009)
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PubMed id:
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Structural basis for antibody discrimination between two hormones that recognize the parathyroid hormone receptor.
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W.J.McKinstry,
G.Polekhina,
H.Diefenbach-Jagger,
P.W.Ho,
K.Sato,
E.Onuma,
M.T.Gillespie,
T.J.Martin,
M.W.Parker.
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ABSTRACT
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Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic
development of the skeleton and other tissues. When it is produced in excess by
cancers it can cause hypercalcemia, and its local production by breast cancer
cells has been implicated in the pathogenesis of bone metastasis formation in
that disease. Antibodies have been developed that neutralize the action of PTHrP
through its receptor, parathyroid hormone receptor 1, without influencing
parathyroid hormone action through the same receptor. Such neutralizing
antibodies against PTHrP are therapeutically effective in animal models of the
humoral hypercalcemia of malignancy and of bone metastasis formation. We have
determined the crystal structure of the complex between PTHrP (residues 1-108)
and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of
contact is an alpha-helical structure extending from residues 14-29. Another
striking feature is that the same residues that interact with the antibody also
interact with parathyroid hormone receptor 1, showing that the antibody and the
receptor binding site on the hormone closely overlap. The structure explains how
the antibody discriminates between the two hormones and provides information
that could be used in the development of novel agonists and antagonists of their
common receptor.
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Selected figure(s)
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Figure 1.
Structure of the PTHrP-antibody complex. a, view of the final
difference (F[obs] − F[calc]) electron density map (blue
transparent surface) in the vicinity of the hormone, at 2.0
Å resolution, calculated using protein phases derived from
the final model after omitting the hormone (and surrounding
atoms within 3 Å of the hormone) and performing a round of
simulated annealing to remove bias. The map is contoured at 3σ
with the final model overlaid upon it. b and c, view of the
complex with the hormone shown in red worm (main chain) and
ball-and-stick (side chain) fashion and the antibody drawn in
ribbon style (the heavy chain is in blue, and light chain is in
orange). b, polar interactions between the N-terminal end of the
hormone with antibody. c, polar and hydrophobic interactions
between the C-terminal end of the hormone with antibody. All
figures were drawn using MOLSCRIPT (42) and RASTER3D (43). The
electron density figure was displayed with the help of CONSCRIPT
(44).
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Figure 2.
Surface representation of the PTHrP binding site colored
according to surface complementarity (40). The most
complimentary fits are shown in red, yellow is average, and
white denotes very poor or no fit. The image was generated with
GRASP (45) and RASTER3D (43).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
15557-15563)
copyright 2009.
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Figures were
selected
by the author.
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Links
