View source for 5oek


==Putative active dimeric state of GHR transmembrane domain==
<StructureSection load='5oek' size='340' side='right'caption='[[5oek]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5oek]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OEK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OEK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR,  models</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=5oek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oek OCA], [https://pdbe.org/5oek PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5oek RCSB], [https://www.ebi.ac.uk/pdbsum/5oek PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5oek ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GHR_HUMAN GHR_HUMAN] Defects in GHR are a cause of Laron syndrome (LARS) [MIM:[https://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:[https://omim.org/entry/604271 604271]. Short stature is defined by a subnormal rate of growth.<ref>PMID:7565946</ref> 
== Function ==
[https://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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== Publication Abstract from PubMed ==
BACKGROUND: Prior studies of the human growth hormone receptor (GHR) revealed a distinct role of spatial rearrangements of its dimeric transmembrane domain in signal transduction across membrane. Detailed structural information obtained in the present study allowed elucidating the bases of such rearrangement and provided novel insights into receptor functioning. METHODS: We investigated the dimerization of recombinant TMD fragment GHR254-294 by means of high-resolution NMR in DPC micelles and molecular dynamics in explicit POPC membrane. RESULTS: We resolved two distinct dimeric structures of GHR TMD coexisting in membrane-mimicking micellar environment and providing left- and right-handed helix-helix association via different dimerization motifs. Based on the available mutagenesis data, the conformations correspond to the dormant and active receptor states and are distinguished by cis-trans isomerization of Phe-Pro(266) bond in the transmembrane helix entry. Molecular dynamic relaxations of the structures in lipid bilayer revealed the role of the proline residue in functionally significant rearrangements of the adjacent juxtamembrane region supporting alternation between protein-protein and protein-lipid interactions of this region that can be triggered by ligand binding. Also, the importance of juxtamembrane SS bonding for signal persistency, and somewhat unusual aspects of transmembrane region interaction with water molecules were demonstrated. CONCLUSIONS: Two alternative dimeric structures of GHR TMD attributed to dormant and active receptor states interchange via allosteric rearrangements of transmembrane helices and extracellular juxtamembrane regions that support coordination between protein-protein and protein-lipid interactions. GENERAL SIGNIFICANCE: This study provides a holistic vision of GHR signal transduction across the membrane emphasizing the role of protein-lipid interactions.

Structural basis of the signal transduction via transmembrane domain of the human growth hormone receptor.,Bocharov EV, Lesovoy DM, Bocharova OV, Urban AS, Pavlov KV, Volynsky PE, Efremov RG, Arseniev AS Biochim Biophys Acta. 2018 Mar 21;1862(6):1410-1420. doi:, 10.1016/j.bbagen.2018.03.022. PMID:29571748<ref>PMID:29571748</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5oek" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arseniev AS]]
[[Category: Bocharov EV]]
[[Category: Bocharova OV]]
[[Category: Lesovoy DM]]
[[Category: Urban AS]]