1kf9

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{{STRUCTURE_1kf9| PDB=1kf9 | SCENE= }}
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==PHAGE DISPLAY DERIVED VARIANT OF HUMAN GROWTH HORMONE COMPLEXED WITH TWO COPIES OF THE EXTRACELLULAR DOMAIN OF ITS RECEPTOR==
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===PHAGE DISPLAY DERIVED VARIANT OF HUMAN GROWTH HORMONE COMPLEXED WITH TWO COPIES OF THE EXTRACELLULAR DOMAIN OF ITS RECEPTOR===
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<StructureSection load='1kf9' size='340' side='right' caption='[[1kf9]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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{{ABSTRACT_PUBMED_11851338}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1kf9]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KF9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1KF9 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1kf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1kf9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1kf9 RCSB], [http://www.ebi.ac.uk/pdbsum/1kf9 PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/GHR_HUMAN GHR_HUMAN]] Defects in GHR are a cause of Laron syndrome (LARS) [MIM:[http://omim.org/entry/262500 262500]]. A severe form of growth hormone insensitivity characterized by growth impairment, short stature, dysfunctional growth hormone receptor, and failure to generate insulin-like growth factor I in response to growth hormone.<ref>PMID:2779634</ref> <ref>PMID:8421103</ref> <ref>PMID:8504296</ref> <ref>PMID:8450064</ref> <ref>PMID:8137822</ref> <ref>PMID:9024232</ref> <ref>PMID:9661642</ref> <ref>PMID:9851797</ref> <ref>PMID:10870033</ref> <ref>PMID:14678285</ref> Defects in GHR may be a cause of idiopathic short stature autosomal (ISSA) [MIM:[http://omim.org/entry/604271 604271]]. Short stature is defined by a subnormal rate of growth.<ref>PMID:7565946</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/GHR_HUMAN GHR_HUMAN]] Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity). The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling. Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kf/1kf9_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The structure of the ternary complex between the phage display- optimized, high-affinity Site 1 variant of human growth hormone (hGH) and two copies of the extracellular domain (ECD) of the hGH receptor (hGHR) has been determined at 2.6 A resolution. There are widespread and significant structural differences compared to the wild-type ternary hGH hGHR complex. The hGH variant (hGH(v)) contains 15 Site 1 mutations and binds&gt;10(2) tighter to the hGHR ECD (hGH(R1)) at Site 1. It is biologically active and specific to hGHR. The hGH(v) Site 1 interface is somewhat smaller and 20% more hydrophobic compared to the wild-type (wt) counterpart. Of the ten hormone-receptor H-bonds in the site, only one is the same as in the wt complex. Additionally, several regions of hGH(v) structure move up to 9A in forming the interface. The contacts between the C-terminal domains of two receptor ECDs (hGH(R1)- hGH(R2)) are conserved; however, the large changes in Site 1 appear to cause global changes in the domains of hGH(R1) that affect the hGH(v)-hGH(R2) interface indirectly. This coupling is manifested by large changes in the conformation of groups participating in the Site 2 interaction and results in a structure for the site that is reorganized extensively. The hGH(v)- hGH(R2) interface contains seven H-bonds, only one of which is found in the wt complex. Several groups on hGH(v) and hGH(R2) undergo conformational changes of up to 8 A. Asp116 of hGH(v) plays a central role in the reorganization of Site 2 by forming two new H-bonds to the side-chains of Trp104(R2) and Trp169(R2), which are the key binding determinants of the receptor. The fact that a different binding solution is possible for Site 2, where there were no mutations or binding selection pressures, indicates that the structural elements found in these molecules possess an inherent functional plasticity that enables them to bind to a wide variety of binding surfaces.
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==Disease==
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Structure of a phage display-derived variant of human growth hormone complexed to two copies of the extracellular domain of its receptor: evidence for strong structural coupling between receptor binding sites.,Schiffer C, Ultsch M, Walsh S, Somers W, de Vos AM, Kossiakoff A J Mol Biol. 2002 Feb 15;316(2):277-89. PMID:11851338<ref>PMID:11851338</ref>
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[[http://www.uniprot.org/uniprot/GHR_HUMAN GHR_HUMAN]] Defects in GHR are a cause of Laron syndrome (LARS) [MIM:[http://omim.org/entry/262500 262500]]. A severe form of growth hormone insensitivity characterized by growth impairment, short stature, dysfunctional growth hormone receptor, and failure to generate insulin-like growth factor I in response to growth hormone.<ref>PMID:2779634</ref><ref>PMID:8421103</ref><ref>PMID:8504296</ref><ref>PMID:8450064</ref><ref>PMID:8137822</ref><ref>PMID:9024232</ref><ref>PMID:9661642</ref><ref>PMID:9851797</ref><ref>PMID:10870033</ref><ref>PMID:14678285</ref> Defects in GHR may be a cause of idiopathic short stature autosomal (ISSA) [MIM:[http://omim.org/entry/604271 604271]]. Short stature is defined by a subnormal rate of growth.<ref>PMID:7565946</ref>
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==Function==
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[[http://www.uniprot.org/uniprot/GHR_HUMAN GHR_HUMAN]] Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity). The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling. Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[1kf9]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KF9 OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:011851338</ref><references group="xtra"/><references/>
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*[[Human growth hormone|Human growth hormone]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Kossiakoff, A A.]]
[[Category: Kossiakoff, A A.]]

Revision as of 16:19, 29 September 2014

PHAGE DISPLAY DERIVED VARIANT OF HUMAN GROWTH HORMONE COMPLEXED WITH TWO COPIES OF THE EXTRACELLULAR DOMAIN OF ITS RECEPTOR

1kf9, resolution 2.60Å

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