Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate.
Nuclear receptors (NRs) comprise the second largest protein family targeted by currently available drugs, acting via specific ligand interactions within the ligand binding domain (LBD). Recently, farnesyl pyrophosphate (FPP) was shown to be a unique promiscuous NR ligand, activating a subset of NR family members and inhibiting wound healing in skin. The current study aimed at visualizing the unique basis of FPP interaction with multiple receptors in order to identify general structure-activity relationships that operate across the NR family. Docking of FPP to the 3D structures of the LBDs of a diverse set of NRs consistently revealed an electrostatic FPP pyrophosphate contact with an NR arginine conserved in the NR family, a hydrophobic farnesyl contact with NR helix-12 and a ligand binding pocket volume between 300 and 430 Å(3) as the minimal requirements for FPP activation of any NR. Lack of any of these structural features appears to render a given NR resistant to FPP activation. We used these structure-activity relationships to rationally design and successfully engineer several mutant human estrogen receptors that retain responsiveness to estradiol but no longer respond to FPP.
Goyanka
Ritu
R
Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Das
Sharmistha
S
Samuels
Herbert H
HH
Cardozo
Timothy
T
D001665:Binding Sites; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D011106:Polyisoprenyl Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate
Nat Struct Biol. 1998 Aug;5(8):679-81
9699629
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):4904-9
11320241
Nature. 1995 Dec 14;378(6558):681-9
7501014
Nature. 1997 Oct 16;389(6652):753-8
9338790
Clin Cancer Res. 2003 Jun;9(6):1980-9
12796359
Mol Endocrinol. 2007 Nov;21(11):2672-86
17666588
Nat Rev Drug Discov. 2006 Dec;5(12):993-6
17139284
Mol Cell Biol. 2000 Jul;20(14):5048-63
10866662
Trends Mol Med. 2002 Feb;8(2):82-8
11815274
J Biol Chem. 2003 Jul 18;278(29):27138-43
12736258
Steroids. 2002 Jan;67(1):15-24
11728517
Genes Dev. 2000 Nov 15;14(22):2831-8
11090131
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5998-6003
9600906
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1008-13
10655475
Nat Rev Drug Discov. 2004 Nov;3(11):950-64
15520817
Gene. 2000 Feb 8;243(1-2):93-103
10675617
Nucleic Acids Res. 1989 Sep 25;17(18):7539
2798115
Nature. 1998 May 28;393(6683):392-6
9620806
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7354-9
12777627
Nat Struct Biol. 1996 Jan;3(1):87-94
8548460
Mol Endocrinol. 1998 Feb;12(2):302-13
9482670
J Biol Chem. 2003 Jun 20;278(25):22748-54
12686538
J Med Chem. 2006 Oct 19;49(21):6151-4
17034119
BMC Struct Biol. 2001;1:1
11405897
J Biol Chem. 2010 Jan 15;285(3):1980-8
19903814
Cell. 1998 Dec 23;95(7):927-37
9875847
J Biol Chem. 2005 Sep 2;280(35):31283-93
15967794
Recent Pat Cardiovasc Drug Discov. 2006 Jan;1(1):21-46
18221072
Ernst Schering Res Found Workshop. 2004;(46):33-45
15248503
Med Sci Monit. 2008 Sep;14(9):RA144-8
18758431
J Med Chem. 1998 May 21;41(11):1803-14
9599231
J Clin Invest. 2007 Aug;117(8):2337-46
17657314
Mol Cell Biol. 1994 Sep;14(9):5756-65
8065310
Bioorg Med Chem. 2009 May 15;17(10):3519-27
19394832
J Med Chem. 2002 May 9;45(10):1963-6
11985463
Cancer Res. 1998 May 1;58(9):1872-5
9581827
EMBO J. 1998 Jan 15;17(2):507-19
9430642