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| | ==Structure of parathyroid hormone-related protein complexed to a neutralizing monoclonal antibody== | | ==Structure of parathyroid hormone-related protein complexed to a neutralizing monoclonal antibody== |
| - | <StructureSection load='3ffd' size='340' side='right' caption='[[3ffd]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='3ffd' size='340' side='right'caption='[[3ffd]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ffd]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FFD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FFD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ffd]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FFD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FFD FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ffd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ffd OCA], [http://pdbe.org/3ffd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ffd RCSB], [http://www.ebi.ac.uk/pdbsum/3ffd PDBsum]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ffd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ffd OCA], [https://pdbe.org/3ffd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ffd RCSB], [https://www.ebi.ac.uk/pdbsum/3ffd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ffd ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PTHR_HUMAN PTHR_HUMAN]] Defects in PTHLH are the cause of brachydactyly type E2 (BDE2) [MIM:[http://omim.org/entry/613382 613382]]. BDE2 is a form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. In brachydactyly type E2 variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges.<ref>PMID:20170896</ref> | + | [https://www.uniprot.org/uniprot/PTHR_HUMAN PTHR_HUMAN] Defects in PTHLH are the cause of brachydactyly type E2 (BDE2) [MIM:[https://omim.org/entry/613382 613382]. BDE2 is a form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. In brachydactyly type E2 variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges.<ref>PMID:20170896</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PTHR_HUMAN PTHR_HUMAN]] Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Upregulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath (By similarity). Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1-dependent manner through activation of Rac1.<ref>PMID:20637541</ref> Osteostatin is a potent inhibitor of osteoclastic bone resorption.<ref>PMID:20637541</ref> | + | [https://www.uniprot.org/uniprot/PTHR_HUMAN PTHR_HUMAN] Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Upregulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath (By similarity). Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1-dependent manner through activation of Rac1.<ref>PMID:20637541</ref> Osteostatin is a potent inhibitor of osteoclastic bone resorption.<ref>PMID:20637541</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ff/3ffd_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ff/3ffd_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | ==See Also== | | ==See Also== |
| - | *[[Monoclonal Antibody|Monoclonal Antibody]] | + | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Diefenbach-Jagger, H]] | + | [[Category: Mus musculus]] |
| - | [[Category: Gillespie, M T]] | + | [[Category: Diefenbach-Jagger H]] |
| - | [[Category: Ho, P W.M]] | + | [[Category: Gillespie MT]] |
| - | [[Category: Martin, T J]] | + | [[Category: Ho PWM]] |
| - | [[Category: Mckinstry, W J]] | + | [[Category: Martin TJ]] |
| - | [[Category: Onuma, E]] | + | [[Category: Mckinstry WJ]] |
| - | [[Category: Parker, M W]] | + | [[Category: Onuma E]] |
| - | [[Category: Polekhina, G]] | + | [[Category: Parker MW]] |
| - | [[Category: Sato, K]] | + | [[Category: Polekhina G]] |
| - | [[Category: Cleavage on pair of basic residue]]
| + | [[Category: Sato K]] |
| - | [[Category: Hormone]]
| + | |
| - | [[Category: Immune system-hormone complex]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Pthrp complexed to fab]]
| + | |
| - | [[Category: Secreted]]
| + | |
| Structural highlights
Disease
PTHR_HUMAN Defects in PTHLH are the cause of brachydactyly type E2 (BDE2) [MIM:613382. BDE2 is a form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. In brachydactyly type E2 variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges.[1]
Function
PTHR_HUMAN Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Upregulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath (By similarity). Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1-dependent manner through activation of Rac1.[2] Osteostatin is a potent inhibitor of osteoclastic bone resorption.[3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Structural basis for antibody discrimination between two hormones that recognize the parathyroid hormone receptor.,McKinstry WJ, Polekhina G, Diefenbach-Jagger H, Ho PW, Sato K, Onuma E, Gillespie MT, Martin TJ, Parker MW J Biol Chem. 2009 Jun 5;284(23):15557-63. doi: 10.1074/jbc.M900044200. Epub 2009 , Apr 4. PMID:19346515[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Klopocki E, Hennig BP, Dathe K, Koll R, de Ravel T, Baten E, Blom E, Gillerot Y, Weigel JF, Kruger G, Hiort O, Seemann P, Mundlos S. Deletion and point mutations of PTHLH cause brachydactyly type E. Am J Hum Genet. 2010 Mar 12;86(3):434-9. doi: 10.1016/j.ajhg.2010.01.023. Epub, 2010 Feb 18. PMID:20170896 doi:10.1016/j.ajhg.2010.01.023
- ↑ Mula RV, Bhatia V, Falzon M. PTHrP promotes colon cancer cell migration and invasion in an integrin alpha6beta4-dependent manner through activation of Rac1. Cancer Lett. 2010 Dec 1;298(1):119-27. doi: 10.1016/j.canlet.2010.06.009. Epub, 2010 Jul 15. PMID:20637541 doi:10.1016/j.canlet.2010.06.009
- ↑ Mula RV, Bhatia V, Falzon M. PTHrP promotes colon cancer cell migration and invasion in an integrin alpha6beta4-dependent manner through activation of Rac1. Cancer Lett. 2010 Dec 1;298(1):119-27. doi: 10.1016/j.canlet.2010.06.009. Epub, 2010 Jul 15. PMID:20637541 doi:10.1016/j.canlet.2010.06.009
- ↑ McKinstry WJ, Polekhina G, Diefenbach-Jagger H, Ho PW, Sato K, Onuma E, Gillespie MT, Martin TJ, Parker MW. Structural basis for antibody discrimination between two hormones that recognize the parathyroid hormone receptor. J Biol Chem. 2009 Jun 5;284(23):15557-63. doi: 10.1074/jbc.M900044200. Epub 2009 , Apr 4. PMID:19346515 doi:http://dx.doi.org/10.1074/jbc.M900044200
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