Glukokortikoidni receptor

Nuklearni receptor potfamilije 3, grupa C, član 1 (glukokortikoidni receptor)
Kristalografska struktura DNK vezujućeg domena glukokortikoidnog receptora (DBD, levo, 1R4O​ vezan za DNK) i ligand vezujući domen [LBD, desno, 1M2Z​ vezan za deksametazon (beli štapići) i TIF2 koaktivatorski protein (crveno)]. Isprekidane žute linije predstavljaju interakcije vodoničnog vezivanja između receptora i liganda. 2D struktura deksametazona je takođe prikazana u dole desno.
Dostupne strukture
1M2Z​, 1NHZ​, 1P93​, 3BQD​, 3CLD​, 3E7C​, 3H52​, 3K22​, 3K23​, 4HN5​, 4HN6​
Identifikatori
Simboli NR3C1; GCCR; GCR; GR; GRL
Vanjski ID OMIM: 138040 MGI: 95824 HomoloGene: 30960 IUPHAR: GeneCards: NR3C1 Gene
Ontologija gena
Molekularna funkcija • za sekvencu specifično dejstvo DNK vezujućeg transkripcionog faktora
• aktivnost glukokortikoidnog receptora
• vezivanje steroida
Celularna komponenta • nukleus
• nukleoplazma
• nukleolus
Biološki proces • regulacija glukoneogeneze
• transkripcija, DNK zavisna
• transkripcija iz promotera RNK polimeraze II
Pregled RNK izražavanja
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 2908 14815
Ensembl ENSG00000113580 ENSMUSG00000024431
UniProt P04150 E9PUR6
RefSeq (mRNA) NM_000176 NM_008173
RefSeq (protein) NP_000167 NP_032199
Lokacija (UCSC) Chr 5:
142.66 - 142.82 Mb		 Chr 18:
39.41 - 39.49 Mb
PubMed pretraga [1] [2]

Glukokortikoidni receptor (GR, GCR, NR3C1, nuklearni receptor potfamilije 3, grupa C, član 1) receptor je za koji se vezuju kortizol i drugi glukokortikoidi.

GR je izražen u skoro svim ćelijma a telu i reguliše gene koji kontrolišu razviće, metabolizam, i imunski respons. Gen ovog receptora se izražava u nekoliko formi, te stoga GR ima mnoštvo različitih (pleiotropskih) dejstava u različitim delovima tela.

Kad se za GR vežu glukokortikoidi, njegov primarni mehanizam dejstva je regulacija trakripcije gena.[1][2] Nevezani receptor se nalazi u ćelijskom citosolu. Nakon vezivanja glukokortikoida za receptor, receptor-glukortikoidni kompleks može da povisi izražavanje antiinflamatornih proteina u jedru ili da suzbije izražavanje proinflamatornih proteina u citozolu (putem sprečavanja translokacije drugih transkripcionih faktora iz citozola u jedro).

Kod ljudi, GR protein je kodiran NR3C1 genom koji je lociran na hromozomu 5 (5q31).[3][4]

Strukture

Poput drugih steroidnih receptora,[5] glukokortikoidni receptor ima modularu strukturu[6] i sadrži sledeće domene (obležene sa A - F):

  • A/B - N-terminal regulatory domain
  • C - DNK vezujući domen (DBD)
  • D - region šarke
  • E - ligand vezujući domen (LBD)
  • F - C-terminalni domen

Vezivanje liganda i odgovor

U odsustvu hormona, glukokortikoidni receptor (GR) se nalazi u citosolu u kompleksu sa raznim proteinima uključujući protein toplotnog šoka 90 (hsp90), protein toplotnog šoka 70 (hsp70) i protein FKBP52 (FK506 vezujući protein 52).[7] Endogeni glukokortikoidni hormon kortizol difuzijom prolazi kroz ćelijsku membranu u citoplazmu i vezuje se za glukokortikoidni receptor (GR), što dovodi do oslobađanja proteina toplotnog šoka. Rezultujuća aktivirana forma GR ima dva moguća mehanizma dejstva, transaktivacija i transrepresija.[8][9]

Transaktivacija

Direktni mehanizam dejstva obuhvata homodimerizaciju receptora, translokaciju putem aktivnog transporta u jedro, i vezivanje za specifiće DNK responsivne elemente, čime se aktivira transkripcija gena. Ovaj mehanizam dejstva se naziva transaktivacija. Biološki respons zavisi od tipa ćelije.

Transrepresija

U odsustvu aktiviranog GR, drugi transkripcini faktori kao što je NF-κB ili AP-1 mogu da transaktiviraju ciljne gene.[10] Aktivirani GR može da formira kompleks as tim drugim transkripcionim faktorima i da spreči njihovo vezivanje za ciljne gene i time suzbije izražavanje gena koje normalno kontrolišu NF-κB ili AP-1. Ovaj indirektni mehanizam dejstva se naziva transrepresija.

Klinički značaj

GR je abnormalan u sučajevima familialne glukokortikoidne otpornosti.[11]

U strukturama centralnog nervnog sistema, glukokortikoidni receptor učestvuje u neuroendokrinoj integraciji. On funkcioniše kao glavna komponenta endokrinog uticaja na mozak, posebno u responsu na stres. Ovaj receptor je impliciran u kratkotrajnu i dugotrajnu adaptaciju u responsu na stresore, i važan je za razumevanje psiholoških poremećaja, uključujući pojedine tipove depresije.[12][13]

Agonisti i antagonisti

Deksametazon je agonist, a RU486 i ciproteron su antagonisti GR. Isto tako, progesteron i DHEA deluju kao antagonisti na GR.

Interacije

Glukokortikoidni receptor može da formira interakcije sa:

Reference

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  • Cadepond F; Gasc JM; Delahaye F; et al. (1992). „Hormonal regulation of the nuclear localization signals of the human glucocorticosteroid receptor.”. Exp. Cell Res. 201 (1): 99—108. PMID 1612132. doi:10.1016/0014-4827(92)90352-9. 
  • Hurley DM; Accili D; Stratakis CA; et al. (1991). „Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.”. J. Clin. Invest. 87 (2): 680—6. PMC 296359 Слободан приступ. PMID 1704018. doi:10.1172/JCI115046. 
  • Encío IJ, Detera-Wadleigh SD (1991). „The genomic structure of the human glucocorticoid receptor.”. J. Biol. Chem. 266 (11): 7182—8. PMID 1707881. 

Vidi još

  • Selektivni agonist glukokortikoidnog receptora (SEGRA)

Spoljašnje veze

  • Human Protein Reference Database
  • Glucocorticoid+receptors на US National Library of Medicine Medical Subject Headings (MeSH)
  • FactorBook GR
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PDB Galerija
  • 1gdc​: Refinirano rešenje strukture DNK vezujućeg domena glikokortikoidnog receptora
    1gdc​: Refinirano rešenje strukture DNK vezujućeg domena glikokortikoidnog receptora
  • 1glu​: Kristalografska analiza interakcija glikokortikoidnog receptora sa DNK
    1glu​: Kristalografska analiza interakcija glikokortikoidnog receptora sa DNK
  • 1m2z​: Kristalna struktura dimernog kompleksa ljudskog ligan vezujućeg domena glukokortikoidnog receptor vezanog za deksametazon i TIF2 koaktivatorski motiv
    1m2z​: Kristalna struktura dimernog kompleksa ljudskog ligan vezujućeg domena glukokortikoidnog receptor vezanog za deksametazon i TIF2 koaktivatorski motiv
  • 1nhz​: Kristalna struktura antagonistne forme glukokortikoidnog receptora
    1nhz​: Kristalna struktura antagonistne forme glukokortikoidnog receptora
  • 1p93​: Kristalna struktura agonistne forme glikokortikoidnog receptora
    1p93​: Kristalna struktura agonistne forme glikokortikoidnog receptora
  • 1r4o​: Kristalografska analiza interakcije glukokortikoidnog receptora sa DNK
    1r4o​: Kristalografska analiza interakcije glukokortikoidnog receptora sa DNK
  • 1r4r​: Kristalografska analiza interakcije glukokortikoidnog receptora sa DNK
    1r4r​: Kristalografska analiza interakcije glukokortikoidnog receptora sa DNK
  • 1rgd​: Refinirano rešenje strukture DNK vezujućeg domena glikokortikoidnog receptora iz NMR podataka putem proračuna relaksacione matrice
    1rgd​: Refinirano rešenje strukture DNK vezujućeg domena glikokortikoidnog receptora iz NMR podataka putem proračuna relaksacione matrice
  • 2gda​: Refinirano rešenje strukture DNK vezujućeg domena glikokortikoidnog receptora
    2gda​: Refinirano rešenje strukture DNK vezujućeg domena glikokortikoidnog receptora
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(1) Osnovni domeni
(1.1) Osnovni leucinski zatvarač (bZIP)
Aktivirajući transkripcioni faktor (AATF, 1, 2, 3, 4, 5, 6, 7) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • BATF • BLZF1 • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3, L1) • CREM • DBP • DDIT3 • GABPA • HLF • MAF (B, F, G, K) • NFE (2, L1, L2) • NFIL3 • NRL • NRF1 • XBP1
(1.2) Osnovni heliks-petlja-heliks (bHLH)
ATOH1 • AhR • AHRR • ARNT • ASCL1 • BHLHB2 • BMAL (ARNTL, ARNTL2) • CLOCK • EPAS1 • HAND (1, 2) • HES (5, 6) • HEY (1, 2, L) • HES1 • HIF (1A, 3A) • ID (1, 2, 3, 4) • LYL1 • MXD4 • MYCL1 • MYCN • Myogenic regulatorni faktori (MyoD, Myogenin, MYF5, MYF6) • Neurogenini (1, 2, 3) • NeuroD (1, 2) • NPAS (1, 2, 3) • OLIG (1, 2) • Pho4 • Scleraxis • TAL (1, 2) • Twist • USF1
(1.3) bHLH-ZIP
AP-4 • MAX • MITF • MNT • MLX • MXI1 • Myc • SREBP (1, 2)
(1.4) NF-1
NFI (A, B, C, X) • SMAD (R-SMAD (1, 2, 3, 5, 9) - I-SMAD (6, 7) - 4)
(1.5) RF-X
RFX (1, 2, 3, 4, 5, ANK)
(1.6) Osnovni heliks-razmak-heliks (bHSH)
AP-2 (α, β, γ, δ, ε)
(2) DNA-vezujući domeni cinkovog prsta
(2.1) Nuklearni receptor (Cys4)
potfamilija 1 (Tiroidni hormon (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR)
potfamilija 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testikularni receptor (2, 4), TLX)
potfamilija 3 (Steroidni hormon (Androgen, Estrogen (α, β), Glukokortikoid, Mineralokortikoid, Progesteron), Estrogen-vezani (α, β, γ))
potfamilija 4 NUR (NGFIB, NOR1, NURR1) • potfamilija 5 (LRH-1, SF1) • potfamilija 6 (GCNF) • potfamilija 0 (DAX1, SHP)
(2.2) Drugi Cys4
GATA (1, 2, 3, 4, 5, 6) • MTA (1, 2, 3) • TRPS1
(2.3) Cys2His2
Generalni transkripcioni faktori (TFIIA, TFIIB, TFIID, TFIIE, TFIIF (1, 2), TFIIH (1, 2, 4, 2I, 3A, 3C1, 3C2))
ATBF1 • BCL (6, 11A, 11B) • CTCF • E4F1 • EGR (2, 3) • ERV3 • GFI1 • GLI-Kruppel familija (1, 2, 3, REST, S2, YY1) • HIC (1, 2) • HIVEP (1, 2, 3) • IKZF (1, 2, 3) • ILF (2, 3) • KLF (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17) • MTF1 • MYT1 • OSR1 • SP (1, 2, 4, 7) • WT1 • Zbtb7 (7A, 7B) • ZBTB (16, 17, 20, 32, 33, 40) • cink prst (3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 318, 330, 346, 350, 365, 366, 384, 423, 451, 452, 471, 593, 638, 649, 655)
(2.4) Cys6
HIVEP1
(2.5) Naizmenična kompozicija
AIRE • DIDO1 • GRLF1 • ING (1, 2, 4) • JARID (1A, 1B, 1C, 1D, 2) • JMJD1B
(3.1) Homeodomen
ARX • CDX (1, 2) • CRX • CUTL1 • DBX (1, 2)  • DLX (3, 4, 5) • EMX2 • EN (1, 2) • FHL (1, 2, 3) • HESX1 • HHEX • HLX • Homeobox (A1, A2, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) • HOPX • IRX (1, 2, 3, 4, 5, 6, MKX) • LMX (1A, 1B) • MEIS (1, 2) • MEOX2 • MNX1 • MSX (1, 2) • NANOG • NKX (2-1, 2-2, 2-3, 2-5, 3-1, 3-2, 6-1, 6-2) • PBX (1, 2, 3) • PHF (1, 3, 6, 8, 10, 16, 17, 20, 21A) • PITX (1, 2, 3) • POU domen (PIT-1, BRN-3: A, B, C, Oktamer transkripcioni faktor: 1, 2, 3/4, 6, 7, 11) • OTX (1, 2) • PDX1 • ZEB (1, 2)
(3.2) Paired box
PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
(3.3) Fork glava / winged heliks
E2F (1, 2, 3, 4, 5) • FOX proteini (C1, C2, D3, E1, G1, H1, K2, L2, M1, N3, O1, O3, O4, P1, P2, P3)
(3.4) Faktori toplotnog šoka
HSF (1, 2, 4)
(3.5) Triptofan klasteri
ELF (2, 4, 5) • EGF • ELK (1, 3, 4) • ERF • ERG • ETS (1, 2, SPIB) • ETV (1, 4, 5, 6) • FLI1 • Interferon regulatorni faktori (1, 2, 3, 4, 5, 6, 7, 8) • MYB • MYBL2
(3.6) TEA domen
transkripcioni pojačivač faktor (1, 2, 3, 4)
(4) β-Scaffold faktori sa manjim žljebnim kontaktima
(4.1) Rel homologni region
NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (C1, C2, C3, C4, 5)
(4.2) STAT
STAT (1, 2, 3, 4, 5, 6)
(4.3) p53
p53 • TBX (1, 2, 3, 5, 19, 21, 22, Brahiuri, TBR1)
(4.4) MADS kutija
Mef2 (A, B, C, D) • SRF
(4.6) TATA vezujući proteini
TBP • TBPL1
(4.7) Grupa visoke pokretljivosti
HMGB (1, 2, 3) • HNF (1A, 1B) • LEF1 • SOX (1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 18, 21) • SRY • SSRP1 • TCF (3, 4) • TOX (1, 2, 3, 4)
(4.10) Domen hladnog šoka
CSDA, YBX1
(4.11) Runt
CBF (CBFA2T2, CBFA2T3, RUNX1, RUNX2, RUNX3, RUNX1T1)
(0) Drugi transkripcioni faktori
(0.2) HMGI(Y)
HMGA (1, 2) • HBP1
(0.3) Džep domen
Rb • RBL1 • RBL2
(0.5) AP-2/EREBP-vezani faktori
Apetala 2 • EREBP • B3
(0.6) Razno
ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • IFI (16, 35) • MLL (2, 3, T1) • MNDA • NFY (A, B, C) • Ro/Sigma
vidi isto transkripcioni faktor/koregulator nedostataka
B bsyn: dnk (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
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Mineralokortikoidi
(3-on, 4-en,
bez fg u 16)
Glukokortikoid
(3-on, 4-en,
11-FG,
17-hidroksi)
Pregnen
Pregnendion
(+20-one)
Pregnadien (+1-en)
Pregnadiendiol
(+21-hidroksi)
Pregnadientriol
(+11-hidroksi)
Pregnatrien
(+2-en)
Androsten
Drugi/negrupisani
Antagonisti aldosterona
Sinteza

M: END

anat/phys/devp/horm/cell

noco(d)/cong/tumr, sysi/epon

proc, lek (A10/H1/H2/H3/H5)