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.
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 NR3C1genom 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):
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]
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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
1nhz: Kristalna struktura antagonistne forme glukokortikoidnog receptora
1p93: Kristalna struktura agonistne forme glikokortikoidnog receptora
1r4o: 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