4zo1

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of the T3-bound TR-beta Ligand-binding Domain in complex with RXR-alpha

Structural highlights

4zo1 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.221Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

THB_HUMAN Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:188570. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17] ^[18] Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:274300. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:145650; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established.^[19] ^[20]

Function

THB_HUMAN High affinity receptor for triiodothyronine.^[21]

Publication Abstract from PubMed

A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using nuclear magnetic resonance (NMR) spectroscopy, x-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show an allosteric mechanism through which RXR co-operates with a permissive dimer partner, peroxisome proliferator-activated receptor (PPAR)-gamma, while rendered generally unresponsive by a non-permissive dimer partner, thyroid hormone (TR) receptor. Amino acid residues that mediate this allosteric mechanism comprise an evolutionarily conserved network discovered by statistical coupling analysis (SCA). This SCA network acts as a signalling rheostat to integrate signals between dimer partners, ligands and coregulator-binding sites, thereby affecting signal transmission in RXR heterodimers. These findings define rules guiding how NRs integrate two ligand-dependent signalling pathways into RXR heterodimer-specific responses.

Structural mechanism for signal transduction in RXR nuclear receptor heterodimers.,Kojetin DJ, Matta-Camacho E, Hughes TS, Srinivasan S, Nwachukwu JC, Cavett V, Nowak J, Chalmers MJ, Marciano DP, Kamenecka TM, Shulman AI, Rance M, Griffin PR, Bruning JB, Nettles KW Nat Commun. 2015 Aug 20;6:8013. doi: 10.1038/ncomms9013. PMID:26289479^[22]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, Bell GI, Refetoff S, DeGroot LJ. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8977-81. PMID:2510172
↑ Usala SJ, Tennyson GE, Bale AE, Lash RW, Gesundheit N, Wondisford FE, Accili D, Hauser P, Weintraub BD. A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. J Clin Invest. 1990 Jan;85(1):93-100. PMID:2153155 doi:http://dx.doi.org/10.1172/JCI114438
↑ Usala SJ, Menke JB, Watson TL, Berard WE, Bradley C, Bale AE, Lash RW, Weintraub BD. A new point mutation in the 3,5,3'-triiodothyronine-binding domain of the c-erbA beta thyroid hormone receptor is tightly linked to generalized thyroid hormone resistance. J Clin Endocrinol Metab. 1991 Jan;72(1):32-8. PMID:1846005
↑ Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD. Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain. J Clin Invest. 1991 Dec;88(6):2123-30. PMID:1661299 doi:http://dx.doi.org/10.1172/JCI115542
↑ Usala SJ, Menke JB, Watson TL, Wondisford FE, Weintraub BD, Berard J, Bradley WE, Ono S, Mueller OT, Bercu BB. A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol Endocrinol. 1991 Mar;5(3):327-35. PMID:1653889
↑ Adams M, Nagaya T, Tone Y, Jameson JL, Chatterjee VK. Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome. Clin Endocrinol (Oxf). 1992 Mar;36(3):281-9. PMID:1563081
↑ Cugini CD Jr, Leidy JW Jr, Chertow BS, Berard J, Bradley WE, Menke JB, Hao EH, Usala SJ. An arginine to histidine mutation in codon 315 of the c-erbA beta thyroid hormone receptor in a kindred with generalized resistance to thyroid hormones results in a receptor with significant 3,5,3'-triiodothyronine binding activity. J Clin Endocrinol Metab. 1992 May;74(5):1164-70. PMID:1314846
↑ Shuto Y, Wakabayashi I, Amuro N, Minami S, Okazaki T. A point mutation in the 3,5,3'-triiodothyronine-binding domain of thyroid hormone receptor-beta associated with a family with generalized resistance to thyroid hormone. J Clin Endocrinol Metab. 1992 Jul;75(1):213-7. PMID:1619012
↑ Sasaki S, Nakamura H, Tagami T, Miyoshi Y, Tanaka K, Imura H. A point mutation of the T3 receptor beta 1 gene in a kindred of generalized resistance to thyroid hormone. Mol Cell Endocrinol. 1992 Apr;84(3):159-66. PMID:1587388
↑ Behr M, Loos U. A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance. Mol Endocrinol. 1992 Jul;6(7):1119-26. PMID:1324420
↑ Weiss RE, Weinberg M, Refetoff S. Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families. J Clin Invest. 1993 Jun;91(6):2408-15. PMID:8514853 doi:http://dx.doi.org/10.1172/JCI116474
↑ Weiss RE, Chyna B, Duell PB, Hayashi Y, Sunthornthepvarakul T, Refetoff S. A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone. J Clin Endocrinol Metab. 1994 May;78(5):1253-6. PMID:8175986
↑ Refetoff S, Weiss RE, Wing JR, Sarne D, Chyna B, Hayashi Y. Resistance to thyroid hormone in subjects from two unrelated families is associated with a point mutation in the thyroid hormone receptor beta gene resulting in the replacement of the normal proline 453 with serine. Thyroid. 1994 Fall;4(3):249-54. PMID:7833659
↑ Pohlenz J, Schonberger W, Wemme H, Winterpacht A, Wirth S, Zabel B. New point mutation (R243W) in the hormone binding domain of the c-erbA beta 1 gene in a family with generalized resistance to thyroid hormone. Hum Mutat. 1996;7(1):79-81. PMID:8664910 doi:<79::AID-HUMU15>3.0.CO;2-P 10.1002/(SICI)1098-1004(1996)7:1<79::AID-HUMU15>3.0.CO;2-P
↑ Seto D, Weintraub BD. Rapid molecular diagnosis of mutations associated with generalized thyroid hormone resistance by PCR-coupled automated direct sequencing of genomic DNA: detection of two novel mutations. Hum Mutat. 1996;8(3):247-57. PMID:8889584 doi:<247::AID-HUMU8>3.0.CO;2-6 10.1002/(SICI)1098-1004(1996)8:3<247::AID-HUMU8>3.0.CO;2-6
↑ Menzaghi C, Di Paola R, Corrias A, Einaudi S, Trischitta V, De Sanctis C, De Filippis V. T426I a new mutation in the thyroid hormone receptor beta gene in a sporadic patient with resistance to thyroid hormone and dysmorphism. Mutations in brief no. 192. Online. Hum Mutat. 1998;12(4):289. PMID:10660344
↑ Mamanasiri S, Yesil S, Dumitrescu AM, Liao XH, Demir T, Weiss RE, Refetoff S. Mosaicism of a thyroid hormone receptor-beta gene mutation in resistance to thyroid hormone. J Clin Endocrinol Metab. 2006 Sep;91(9):3471-7. Epub 2006 Jun 27. PMID:16804041 doi:10.1210/jc.2006-0727
↑ Rivolta CM, Olcese MC, Belforte FS, Chiesa A, Gruneiro-Papendieck L, Iorcansky S, Herzovich V, Cassorla F, Gauna A, Gonzalez-Sarmiento R, Targovnik HM. Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene. Mol Cell Probes. 2009 Jun-Aug;23(3-4):148-53. doi: 10.1016/j.mcp.2009.02.002., Epub 2009 Mar 4. PMID:19268523 doi:10.1016/j.mcp.2009.02.002
↑ Flynn TR, Hollenberg AN, Cohen O, Menke JB, Usala SJ, Tollin S, Hegarty MK, Wondisford FE. A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition. J Biol Chem. 1994 Dec 30;269(52):32713-6. PMID:7528740
↑ Geffner ME, Su F, Ross NS, Hershman JM, Van Dop C, Menke JB, Hao E, Stanzak RK, Eaton T, Samuels HH, et al.. An arginine to histidine mutation in codon 311 of the C-erbA beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype. J Clin Invest. 1993 Feb;91(2):538-46. PMID:8381821 doi:http://dx.doi.org/10.1172/JCI116233
↑ Chou WY, Cheng YS, Ho CL, Liu ST, Liu PY, Kuo CC, Chang HP, Chen YH, Chang GG, Huang SM. Human spot 14 protein interacts physically and functionally with the thyroid receptor. Biochem Biophys Res Commun. 2007 May 25;357(1):133-8. Epub 2007 Mar 26. PMID:17418816 doi:10.1016/j.bbrc.2007.03.103
↑ Kojetin DJ, Matta-Camacho E, Hughes TS, Srinivasan S, Nwachukwu JC, Cavett V, Nowak J, Chalmers MJ, Marciano DP, Kamenecka TM, Shulman AI, Rance M, Griffin PR, Bruning JB, Nettles KW. Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. Nat Commun. 2015 Aug 20;6:8013. doi: 10.1038/ncomms9013. PMID:26289479 doi:http://dx.doi.org/10.1038/ncomms9013

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zo1"

@@ Line 3: / Line 3: @@
 <StructureSection load='4zo1' size='340' side='right'caption='[[4zo1]], [[Resolution|resolution]] 3.22&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zo1]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZO1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZO1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zo1]] is a 3 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=4ZO1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZO1 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=T3:3,5,3TRIIODOTHYRONINE'>T3</scene></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]] 3.221&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">THRB, ERBA2, NR1A2, THR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=T3:3,5,3TRIIODOTHYRONINE'>T3</scene></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=4zo1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zo1 OCA], [http://pdbe.org/4zo1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zo1 RCSB], [http://www.ebi.ac.uk/pdbsum/4zo1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zo1 ProSAT]</span></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=4zo1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zo1 OCA], [https://pdbe.org/4zo1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zo1 RCSB], [https://www.ebi.ac.uk/pdbsum/4zo1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zo1 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN]] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:[http://omim.org/entry/188570 188570]]. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH).<ref>PMID:2510172</ref> <ref>PMID:2153155</ref> <ref>PMID:1846005</ref> <ref>PMID:1661299</ref> <ref>PMID:1653889</ref> <ref>PMID:1563081</ref> <ref>PMID:1314846</ref> <ref>PMID:1619012</ref> <ref>PMID:1587388</ref> <ref>PMID:1324420</ref> <ref>PMID:8514853</ref> <ref>PMID:8175986</ref> <ref>PMID:7833659</ref> <ref>PMID:8664910</ref> <ref>PMID:8889584</ref> <ref>PMID:10660344</ref> <ref>PMID:16804041</ref> <ref>PMID:19268523</ref>   Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:[http://omim.org/entry/274300 274300]]. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone.  Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:[http://omim.org/entry/145650 145650]]; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established.<ref>PMID:7528740</ref> <ref>PMID:8381821</ref>
+[https://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:[https://omim.org/entry/188570 188570]. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH).<ref>PMID:2510172</ref> <ref>PMID:2153155</ref> <ref>PMID:1846005</ref> <ref>PMID:1661299</ref> <ref>PMID:1653889</ref> <ref>PMID:1563081</ref> <ref>PMID:1314846</ref> <ref>PMID:1619012</ref> <ref>PMID:1587388</ref> <ref>PMID:1324420</ref> <ref>PMID:8514853</ref> <ref>PMID:8175986</ref> <ref>PMID:7833659</ref> <ref>PMID:8664910</ref> <ref>PMID:8889584</ref> <ref>PMID:10660344</ref> <ref>PMID:16804041</ref> <ref>PMID:19268523</ref>   Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:[https://omim.org/entry/274300 274300]. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone.  Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:[https://omim.org/entry/145650 145650]; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established.<ref>PMID:7528740</ref> <ref>PMID:8381821</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN]] High affinity receptor for triiodothyronine.<ref>PMID:17418816</ref>  [[http://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN]] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>
+[https://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN] High affinity receptor for triiodothyronine.<ref>PMID:17418816</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 ==See Also==
-*[[Retinoid X receptor|Retinoid X receptor]]
+*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
 *[[Thyroid hormone receptor|Thyroid hormone receptor]]
 == References ==
@@ Line 30: / Line 30: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Bruning, J B]]
+[[Category: Bruning JB]]
-[[Category: Cavett, V]]
+[[Category: Cavett V]]
-[[Category: Chalmers, M J]]
+[[Category: Chalmers MJ]]
-[[Category: Griffin, P R]]
+[[Category: Griffin PR]]
-[[Category: Hughes, T S]]
+[[Category: Hughes TS]]
-[[Category: Kamenecka, T M]]
+[[Category: Kamenecka TM]]
-[[Category: Kojetin, D J]]
+[[Category: Kojetin DJ]]
-[[Category: Mangelsdorf, D J]]
+[[Category: Mangelsdorf DJ]]
-[[Category: Marciano, D P]]
+[[Category: Marciano DP]]
-[[Category: Matta-Camacho, E]]
+[[Category: Matta-Camacho E]]
-[[Category: Nettles, K W]]
+[[Category: Nettles KW]]
-[[Category: Nowak, J]]
+[[Category: Nowak J]]
-[[Category: Nwachukwu, J C]]
+[[Category: Nwachukwu JC]]
-[[Category: Rance, M]]
+[[Category: Rance M]]
-[[Category: Shulman, A I]]
+[[Category: Shulman AI]]
-[[Category: Srinivasan, S]]
+[[Category: Srinivasan S]]
-[[Category: Ligand binding]]
-[[Category: Nuclear receptor]]
-[[Category: Protein binding]]
-[[Category: Protein-ligand complex]]
-[[Category: Transcription factor]]

4zo1

From Proteopedia

Current revision

Crystal Structure of the T3-bound TR-beta Ligand-binding Domain in complex with RXR-alpha

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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