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| - | [[Image:1a22.jpg|left|200px]]<br /><applet load="1a22" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1a22, resolution 2.6Å" /> | |
| - | '''HUMAN GROWTH HORMONE BOUND TO SINGLE RECEPTOR'''<br /> | |
| | | | |
| - | ==Overview== | + | ==HUMAN GROWTH HORMONE BOUND TO SINGLE RECEPTOR== |
| - | The designed G120R mutant of human growth hormone (hGH) is an antagonist, and can bind only one molecule of the growth hormone receptor. We have, determined the crystal structure of the 1:1 complex between this mutant, and the receptor extracellular domain (hGHbp) at 2.6 A resolution, and, used it to guide a detailed survey of the structural and functional basis, for hormone-receptor recognition. The overall structure of the complex is, very similar to the equivalent portion of the 1:2 complex, showing that, formation of the active complex does not involve major conformational, changes. However, a segment involved in receptor-receptor interactions in, the 1:2 complex is disordered in this structure, suggesting that its, productive conformation is stabilized by receptor dimerization.The hormone, binding site of the receptor comprises a central hydrophobic patch, dominated by Trp104 and Trp169, surrounded by a hydrophilic periphery, containing several well-ordered water molecules. Previous alanine scanning, showed that the hydrophobic "hot spot" confers most of the binding energy., The new structural data, coupled with binding and kinetic analysis of, further mutants, indicate that the hot spot is assembled cooperatively and, that many residues contribute indirectly to binding. Several hydrophobic, residues serve to orient the key tryptophan residues; kinetic analysis, suggests that Pro106 locks the Trp104 main-chain into a required, conformation. The electrostatic contacts of Arg43 to hGH are less, important than the intramolecular packing of its alkyl chain with Trp169., The true functional epitope that directly contributes binding energy may, therefore comprise as few as six side-chains, participating mostly in, alkyl-aromatic stacking interactions. Outside the functional epitope, multiple mutation of residues to alanine resulted in non-additive, increases in affinity: up to tenfold for a hepta-alanine mutant. Contacts, in the epitope periphery can therefore attenuate the affinity of the, central hot spot, perhaps reflecting a role in conferring specificity to, the interaction. | + | <StructureSection load='1a22' size='340' side='right'caption='[[1a22]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1a22]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A22 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1A22 FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</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=1a22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1a22 OCA], [https://pdbe.org/1a22 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1a22 RCSB], [https://www.ebi.ac.uk/pdbsum/1a22 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1a22 ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/SOMA_HUMAN SOMA_HUMAN] Defects in GH1 are a cause of growth hormone deficiency isolated type 1A (IGHD1A) [MIM:[https://omim.org/entry/262400 262400]; also known as pituitary dwarfism I. IGHD1A is an autosomal recessive deficiency of GH which causes short stature. IGHD1A patients have an absence of GH with severe dwarfism and often develop anti-GH antibodies when given exogenous GH.<ref>PMID:8364549</ref> Defects in GH1 are a cause of growth hormone deficiency isolated type 1B (IGHD1B) [MIM:[https://omim.org/entry/612781 612781]; also known as dwarfism of Sindh. IGHD1B is an autosomal recessive deficiency of GH which causes short stature. IGHD1B patients have low but detectable levels of GH. Dwarfism is less severe than in IGHD1A and patients usually respond well to exogenous GH. Defects in GH1 are the cause of Kowarski syndrome (KWKS) [MIM:[https://omim.org/entry/262650 262650]; also known as pituitary dwarfism VI.<ref>PMID:8552145</ref> <ref>PMID:9276733</ref> <ref>PMID:17519310</ref> Defects in GH1 are a cause of growth hormone deficiency isolated type 2 (IGHD2) [MIM:[https://omim.org/entry/173100 173100]. IGHD2 is an autosomal dominant deficiency of GH which causes short stature. Clinical severity is variable. Patients have a positive response and immunologic tolerance to growth hormone therapy. |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/SOMA_HUMAN SOMA_HUMAN] Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues. |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a2/1a22_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </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/main_output.php?pdb_ID=1a22 ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The designed G120R mutant of human growth hormone (hGH) is an antagonist and can bind only one molecule of the growth hormone receptor. We have determined the crystal structure of the 1:1 complex between this mutant and the receptor extracellular domain (hGHbp) at 2.6 A resolution, and used it to guide a detailed survey of the structural and functional basis for hormone-receptor recognition. The overall structure of the complex is very similar to the equivalent portion of the 1:2 complex, showing that formation of the active complex does not involve major conformational changes. However, a segment involved in receptor-receptor interactions in the 1:2 complex is disordered in this structure, suggesting that its productive conformation is stabilized by receptor dimerization. The hormone binding site of the receptor comprises a central hydrophobic patch dominated by Trp104 and Trp169, surrounded by a hydrophilic periphery containing several well-ordered water molecules. Previous alanine scanning showed that the hydrophobic "hot spot" confers most of the binding energy. The new structural data, coupled with binding and kinetic analysis of further mutants, indicate that the hot spot is assembled cooperatively and that many residues contribute indirectly to binding. Several hydrophobic residues serve to orient the key tryptophan residues; kinetic analysis suggests that Pro106 locks the Trp104 main-chain into a required conformation. The electrostatic contacts of Arg43 to hGH are less important than the intramolecular packing of its alkyl chain with Trp169. The true functional epitope that directly contributes binding energy may therefore comprise as few as six side-chains, participating mostly in alkyl-aromatic stacking interactions. Outside the functional epitope, multiple mutation of residues to alanine resulted in non-additive increases in affinity: up to tenfold for a hepta-alanine mutant. Contacts in the epitope periphery can therefore attenuate the affinity of the central hot spot, perhaps reflecting a role in conferring specificity to the interaction. |
| | | | |
| - | ==Disease==
| + | Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity.,Clackson T, Ultsch MH, Wells JA, de Vos AM J Mol Biol. 1998 Apr 17;277(5):1111-28. PMID:9571026<ref>PMID:9571026</ref> |
| - | Known diseases associated with this structure: Growth hormone deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=139250 139250]], Growth hormone deficiency, isolated, type IA OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=139250 139250]], Growth hormone deficiency, isolated, type IB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=139250 139250]], Growth hormone deficiency, isolated, type II OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=139250 139250]], Increased responsiveness to growth hormone OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]], Kowarski syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=139250 139250]], Laron dwarfism OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]], Short stature, autosomal dominant, with normal serum growth hormone binding protein OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]], Short stature, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=139250 139250]], Short stature, idiopathic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600946 600946]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1A22 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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=1A22 OCA].
| + | </div> |
| | + | <div class="pdbe-citations 1a22" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity., Clackson T, Ultsch MH, Wells JA, de Vos AM, J Mol Biol. 1998 Apr 17;277(5):1111-28. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9571026 9571026]
| + | *[[Human growth hormone|Human growth hormone]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Ultsch, M.]] | + | [[Category: De Vos AM]] |
| - | [[Category: Vos, A.M.De.]] | + | [[Category: Ultsch M]] |
| - | [[Category: complex (hormone/receptor)]]
| + | |
| - | [[Category: hormone]]
| + | |
| - | [[Category: pituitary]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 15:28:09 2008''
| + | |
| Structural highlights
Disease
SOMA_HUMAN Defects in GH1 are a cause of growth hormone deficiency isolated type 1A (IGHD1A) [MIM:262400; also known as pituitary dwarfism I. IGHD1A is an autosomal recessive deficiency of GH which causes short stature. IGHD1A patients have an absence of GH with severe dwarfism and often develop anti-GH antibodies when given exogenous GH.[1] Defects in GH1 are a cause of growth hormone deficiency isolated type 1B (IGHD1B) [MIM:612781; also known as dwarfism of Sindh. IGHD1B is an autosomal recessive deficiency of GH which causes short stature. IGHD1B patients have low but detectable levels of GH. Dwarfism is less severe than in IGHD1A and patients usually respond well to exogenous GH. Defects in GH1 are the cause of Kowarski syndrome (KWKS) [MIM:262650; also known as pituitary dwarfism VI.[2] [3] [4] Defects in GH1 are a cause of growth hormone deficiency isolated type 2 (IGHD2) [MIM:173100. IGHD2 is an autosomal dominant deficiency of GH which causes short stature. Clinical severity is variable. Patients have a positive response and immunologic tolerance to growth hormone therapy.
Function
SOMA_HUMAN Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.
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
The designed G120R mutant of human growth hormone (hGH) is an antagonist and can bind only one molecule of the growth hormone receptor. We have determined the crystal structure of the 1:1 complex between this mutant and the receptor extracellular domain (hGHbp) at 2.6 A resolution, and used it to guide a detailed survey of the structural and functional basis for hormone-receptor recognition. The overall structure of the complex is very similar to the equivalent portion of the 1:2 complex, showing that formation of the active complex does not involve major conformational changes. However, a segment involved in receptor-receptor interactions in the 1:2 complex is disordered in this structure, suggesting that its productive conformation is stabilized by receptor dimerization. The hormone binding site of the receptor comprises a central hydrophobic patch dominated by Trp104 and Trp169, surrounded by a hydrophilic periphery containing several well-ordered water molecules. Previous alanine scanning showed that the hydrophobic "hot spot" confers most of the binding energy. The new structural data, coupled with binding and kinetic analysis of further mutants, indicate that the hot spot is assembled cooperatively and that many residues contribute indirectly to binding. Several hydrophobic residues serve to orient the key tryptophan residues; kinetic analysis suggests that Pro106 locks the Trp104 main-chain into a required conformation. The electrostatic contacts of Arg43 to hGH are less important than the intramolecular packing of its alkyl chain with Trp169. The true functional epitope that directly contributes binding energy may therefore comprise as few as six side-chains, participating mostly in alkyl-aromatic stacking interactions. Outside the functional epitope, multiple mutation of residues to alanine resulted in non-additive increases in affinity: up to tenfold for a hepta-alanine mutant. Contacts in the epitope periphery can therefore attenuate the affinity of the central hot spot, perhaps reflecting a role in conferring specificity to the interaction.
Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity.,Clackson T, Ultsch MH, Wells JA, de Vos AM J Mol Biol. 1998 Apr 17;277(5):1111-28. PMID:9571026[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Igarashi Y, Ogawa M, Kamijo T, Iwatani N, Nishi Y, Kohno H, Masumura T, Koga J. A new mutation causing inherited growth hormone deficiency: a compound heterozygote of a 6.7 kb deletion and a two base deletion in the third exon of the GH-1 gene. Hum Mol Genet. 1993 Jul;2(7):1073-4. PMID:8364549
- ↑ Takahashi Y, Kaji H, Okimura Y, Goji K, Abe H, Chihara K. Brief report: short stature caused by a mutant growth hormone. N Engl J Med. 1996 Feb 15;334(7):432-6. PMID:8552145 doi:http://dx.doi.org/10.1056/NEJM199602153340704
- ↑ Takahashi Y, Shirono H, Arisaka O, Takahashi K, Yagi T, Koga J, Kaji H, Okimura Y, Abe H, Tanaka T, Chihara K. Biologically inactive growth hormone caused by an amino acid substitution. J Clin Invest. 1997 Sep 1;100(5):1159-65. PMID:9276733 doi:10.1172/JCI119627
- ↑ Petkovic V, Besson A, Thevis M, Lochmatter D, Eble A, Fluck CE, Mullis PE. Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature. J Clin Endocrinol Metab. 2007 Aug;92(8):2893-901. Epub 2007 May 22. PMID:17519310 doi:10.1210/jc.2006-2238
- ↑ Clackson T, Ultsch MH, Wells JA, de Vos AM. Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity. J Mol Biol. 1998 Apr 17;277(5):1111-28. PMID:9571026 doi:10.1006/jmbi.1998.1669
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