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The estrogen-related receptor (ERR) γ behaves as a constitutive activator of transcription. Although no natural ligand is known, ERRγ is deactivated by the estrogen receptor (ER) agonist diethylstilbestrol and the selective ER modulator 4-hydroxytamoxifen but does not significantly respond to estradiol or raloxifene. Here we report the crystal structures of the ERRγ ligand binding domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to ERRγ results in a rotation of the side chain of Phe-435 that partially fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces the “activation helix” (helix 12) from the agonist position observed in the absence of ligand. In contrast to the complexes of the ERα LBD with 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERRγ does not occupy the coactivator groove but appears to be completely dissociated from the LBD body. Comparison of the ligand-bound LBDs of ERRγ and ERα reveals small but significant differences in the architecture of the ligand binding pockets that result in a slightly shifted binding position of diethylstilbestrol and a small rotation of 4-hydroxytamoxifen in the cavity of ERRγ relative to ERα. Our results provide detailed molecular insight into the conformational changes occurring upon binding of synthetic antagonists to the constitutive orphan receptor ERRγ and reveal structural differences with ERs that explain why ERRγ does not bind estradiol or raloxifene and will help to design new selective antagonists. The estrogen-related receptor (ERR) γ behaves as a constitutive activator of transcription. Although no natural ligand is known, ERRγ is deactivated by the estrogen receptor (ER) agonist diethylstilbestrol and the selective ER modulator 4-hydroxytamoxifen but does not significantly respond to estradiol or raloxifene. Here we report the crystal structures of the ERRγ ligand binding domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to ERRγ results in a rotation of the side chain of Phe-435 that partially fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces the “activation helix” (helix 12) from the agonist position observed in the absence of ligand. In contrast to the complexes of the ERα LBD with 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERRγ does not occupy the coactivator groove but appears to be completely dissociated from the LBD body. Comparison of the ligand-bound LBDs of ERRγ and ERα reveals small but significant differences in the architecture of the ligand binding pockets that result in a slightly shifted binding position of diethylstilbestrol and a small rotation of 4-hydroxytamoxifen in the cavity of ERRγ relative to ERα. Our results provide detailed molecular insight into the conformational changes occurring upon binding of synthetic antagonists to the constitutive orphan receptor ERRγ and reveal structural differences with ERs that explain why ERRγ does not bind estradiol or raloxifene and will help to design new selective antagonists. The estrogen-related receptors ERRα, 1The abbreviations used are: ERR, estrogen-related receptor; ER, estrogen receptor; AF, activation function; AU, asymmetric unit; DES, diethylstilbestrol; E2, estradiol; H, α-helix; 4-OHT, 4-hydroxytamoxifen; ICI, ICI 164,384; LBD, ligand binding domain; LBP, ligand binding pocket; RAL, raloxifene; SERM, selective estrogen receptor modulator; SRC-1, steroid receptor coactivator-1; MES, 4-morpholine-ethanesulfonic acid; PEG, polyethylene glycol. ERRβ, and ERRγ (NR3B1, -2, and -3) (1Committee The Nuclear Receptor Nomenclature Cell. 1999; 97: 161-163Abstract Full Text Full Text PDF PubMed Scopus (963) Google Scholar) form a subfamily of orphan nuclear receptors that share significant amino acid homology with the estrogen receptors ERα and ERβ (NR3A1 and -2) (2Giguère V. Trends Endocrinol. Metab. 2002; 13: 220-225Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 3Horard B. Vanacker J.M. J. Mol. Endocrinol. 2003; 31: 349-357Crossref PubMed Scopus (206) Google Scholar). Because of the high conservation in the DNA binding domain, ERRs and ERs have overlapping DNA binding selectivity (4Pettersson K. Svensson K. Mattsson R. Carlsson B. Ohlsson R. Berkenstam A. Mech. Dev. 1996; 54: 211-223Crossref PubMed Scopus (120) Google Scholar, 5Yang N. Shigeta H. Shi H. Teng C.T. J. Biol. Chem. 1996; 271: 5795-5804Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 6Johnston S.D. Liu X. Zuo F. Eisenbraun T.L. Wiley S.R. Kraus R.J. Mertz J.E. Mol. Endocrinol. 1997; 11: 342-352Crossref PubMed Scopus (164) Google Scholar) and, accordingly, may co-regulate target genes in tissues in which they are co-expressed. ERR subfamily members have for example been shown to modulate the expression of ER target genes in bone (7Vanacker J.M. Petterson K. Gustafsson J.A. Laudet V. EMBO J. 1999; 18: 4270-4279Crossref PubMed Scopus (296) Google Scholar, 8Bonnelye E. Kung V. Laplace C. Galson D.L. Aubin J.E. Endocrinology. 2002; 143: 3658-3670Crossref PubMed Scopus (54) Google Scholar) or breast tissue (9Lu D. Kiriyama Y. Lee K.Y. Giguère V. Cancer Res. 2001; 61: 6755-6761PubMed Google Scholar, 10Kraus R.J. Ariazi E.A. Farrel M.L. Mertz J.E. J. Biol. Chem. 2002; 277: 24826-24834Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Importantly, overexpression of ERRα and ERRγ in samples from breast cancer patients correlates with unfavorable and favorable biomarkers, respectively (11Ariazi E.A. Clark G.M. Mertz J.E. Cancer Res. 2002; 62: 6510-6518PubMed Google Scholar). Therefore, these receptors might serve as prognostic markers themselves or even be targets for endocrine therapy in human breast cancer. Despite their significant homology with ERs in the ligand binding domain (LBD), ERRs do not (or only very weakly) respond to estradiol (E2) (2Giguère V. Trends Endocrinol. Metab. 2002; 13: 220-225Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). Furthermore, whereas ERs are ligand-activated receptors, ERRs are constitutively active (13Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 14Vanacker J.M. Bonnelye E. Chopin-Delannoy S. Delmarre C. Cavailles V. Laudet V. Mol. Endocrinol. 1999; 13: 764-773PubMed Google Scholar, 15Xie W. Hong H. Yang N.N. Lin R.J. Simon C.M. Stallcup M.R. Evans R.M. Mol. Endocrinol. 1999; 13: 1594-1604Crossref Scopus (129) Google Scholar, 16Chen S. Zhou D. Yang C. Sherman M. J. Biol. Chem. 2001; 276: 28465-28470Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar), and a structural study confirmed that the ERRγ LBD can adopt a transcriptionally active conformation and interact with the steroid receptor coactivator 1 (SRC-1) in the absence of any ligand (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). Together, these observations suggest that ERRs are ligand-independent activators of transcription whose activation potential may rather be determined by the presence of transcriptional coactivators (17Hentschke M. Süsens U. Borgmeyer U. Biochem. Biophys. Res. 2002; PubMed Scopus Google Scholar, J.M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, D. K. A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. H. Y. N. M. A. U. S. A. 2003; PubMed Scopus Google Scholar). Although natural ERR may not to as antagonists to the architecture of the ligand binding observed for the ERRγ (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). Although no natural ligand is to the ER agonist diethylstilbestrol and the selective ER modulator 4-hydroxytamoxifen have been as ERR antagonists D. L. C. J.A. J. Giguère V. Dev. 2001; PubMed Scopus Google Scholar, D. Giguère V. Endocrinology. 2001; PubMed Scopus Google Scholar, Lee D. J. U. S. A. 2001; PubMed Scopus Google Scholar). whereas only to and In the raloxifene does not bind to ERRs Lee D. J. U. S. A. 2001; PubMed Scopus Google Scholar) in The of ERRα is by the and C. S. Cancer Res. 1999; Google Scholar), but binding of these to ERRα D. L. C. J.A. J. Giguère V. Dev. 2001; PubMed Scopus Google Scholar). In to (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar), a study and as ERR M. L. K. S. Mol. Cancer Res. 2003; Google Scholar), binding of these to the receptors not been of the of ERs and in a new Nuclear receptor LBDs adopt a of 12 and a small Renaud Moras D. Biophys. 2001; PubMed Scopus Google Scholar, H. Moras D. Chem. 2003; PubMed Scopus Google Scholar). the LBD activation by a conformation in which the LBD and with and a coactivator binding bind and any amino that form Antagonist with the of active LBD conformation and coactivator In is a ligand from the and in the agonist as by the ERα LBD to or L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) or the ERβ LBD complexed with ICI J. Gustafsson J.A. M. 2001; 9: Full Text Full Text PDF PubMed Scopus Google Scholar). antagonists can the active LBD conformation by and the LBD as by the of ERβ D. J.A. Biol. 2002; 9: Google Scholar). In and been to the conformation of the antagonist-bound ER LBD with the by or ER antagonists in L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Gustafsson J.A. M. 2001; 9: Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. Mol. Endocrinol. 2003; PubMed Scopus Google Scholar). In the complexes of the ERα LBD with or a of the of and structural of the to bind to the coactivator groove L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In in the ERβ is not to high the of the ligand the coactivator groove J. Gustafsson J.A. M. 2001; 9: Full Text Full Text PDF PubMed Scopus Google Scholar). In a high appears to result in ER in for the of ICI J. Gustafsson J.A. M. 2001; 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S. R. U. S. A. PubMed Scopus Google Scholar). confirmed a of the of in ERα complexes in J.A. Mol. Endocrinol. 2003; PubMed Scopus Google Scholar). antagonists to have a potential and differences observed the of and In contrast to is conformational changes of ERR Here we report the crystal structures of the ERRγ and of ERRγ complexes and of the antagonist-bound structures with the ERRγ to in the transcriptionally active conformation the conformational changes occurring upon or Comparison of the ERRγ complexes with the ERα LBD to DES, 4-OHT, reveals differences in the architecture of the of ERα and ERRγ that do not binding of or to results suggest that observed in the complexes of the ERα LBD with and a with the of coactivators to antagonist-bound and ERRγ LBD from a expression in of the and the by in a in of the with the ERRγ LBD by the to The by a a The LBD in from the the position as a The and to and with a of or with the or the of of of in 1 of 1 of of in the ERRγ and of the ERRγ the of crystal form for the ERRγ upon with the In the ERRγ in a with a ERRγ form in with a ERRγ of form in in of the ERRγ in the presence of a of a coactivator (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar) in with a as the the or the the in The and the W. 1997; 276: PubMed Scopus Google Scholar). and crystal structures of the ERRγ and the ERRγ complexes by molecular with J. A. Scopus Google Scholar) the ERRγ LBD (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar) as the The structures the G.M. J. M. R.J. D. 54: PubMed Scopus Google Scholar) and of the D. PubMed Scopus Google Scholar, D. 1997; PubMed Scopus Google Scholar, A. M. D. 2001; PubMed Scopus Google Scholar, E. M. E. D. 2003; PubMed Scopus Google Scholar). and of the the M. A. PubMed Scopus Google Scholar). The with J.M. J. Google Scholar). and are in the of the from in in to the of in in the of and The of the ERRγ in the absence and presence of ligand with D. PubMed Scopus Google Scholar). The with structural and form form in are for the in are for the in are for the is the of the observations for the of is in the in in are for the is the of the observations for the of is in the in a new of the ERRγ the crystal structures of the ERRγ LBD in with of and with form 1 crystal form In we the of the ERRγ to a (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar) of In the ERRγ LBD in ligand binding does not with Comparison of the ERRγ with the and complexes no conformational changes for the chain from to the of not changes of the chain of the which result from crystal In structural of the chain to or binding the of the and in the ligand-bound the of is slightly from the of the to of the ligand. in of the ERRγ not the ERRγ complexes in the asymmetric the of is In contrast to ERα complexes L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), is not observed in the ERRγ complexes but is only in in crystal in ligand-bound complexes the or is in The to the by the position and conformation of and of the of by crystal by crystal from groove of groove of form in a new In contrast to the complexes of the ERα LBD with and L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), in of the ERRγ complexes does the coactivator groove of LBD body. is not to high in the of the ERRγ form and with the coactivator groove of a in crystal form and in the of crystal form conformational of the and the of the In the ERRγ the is not or is in of of the is crystal in a position that the agonist conformation in the ERRγ in of is shifted by the with to the agonist position in the ERRγ a the conformation of the is completely and a position that in is not by favorable Together, these observations suggest that in or binding the of whose conformation and position in the is determined by of and of or bind the small ERRγ observed in the (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). binding structural that the of the ERRγ to The binding from the cavity the which the The conformational the in to and binding is a rotation of the side chain of Phe-435 which for the in cavity The new rotamer of Phe-435 with in the agonist with the side chain of in the or rotation of the side chain of Phe-435 of the transcriptionally active conformation of the ERRγ LBD, which coactivator The binding of or is by amino acid from the and and not The of with and Phe-435 not Furthermore, the side chain of the ERRγ LBD to form a with the of which been observed with in the ERα D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). in the ERα complexes D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and are side of the by with and with the side of the Importantly, the side chain of whose position is not in the ERRγ to high the ligand and is in the and the In and only slightly upon ligand small structural changes the relative to the the side of and a which to of the ligand. of the and complexes of the ERRγ LBD that the the of with the or of reveals a small of by which of can the the ERRγ Comparison with ERα and of reveals of binding to ERRγ and the the complexes a agonist position in the of ERα but in the of ERRγ binding does not with the agonist position in ERα the side chain of to Phe-435 in to the ligand a conformational the binding position of is slightly shifted by in the ERRγ relative to the ERα result from differences in the relative of and, the of the the that to the and the with only In significant of the helix are observed for and of ERRγ and the in the ERRγ LBP, which may be the of the slightly binding Importantly, with DES, the binding position significantly in the of ERα and ERRγ Although the binding is and the ligand and of the in the binding for the and the by and Phe-435 in ERRγ to and in to a small rotation of the in the binding position in the of as observed in result in with and Phe-435 differences in the architecture of the of ERRγ and ERα provide a why and do not bind to ERRγ with significant of ERα LBDs in with that and into the and in conformational side chain of L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In appears that the of the in the cavity of ERRγ by the shifted position of be in favorable by a conformational of the side chain of the position of and the presence of in ERRγ in to for the of or binding to In of the ERRγ the of the of a by a we the groove in the complexes of ERRγ form and ERα. In ERα LBD and coactivator binding by and into the coactivator D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In in ERRγ the of with the LBD of a is determined by the presence of a the to as acid (or a The acid is to the of the the of the of and with the of the coactivator groove Comparison of ERRγ the that and the of whereas the and the of adopt to relative and not In the of of ERRγ with the coactivator in a as the in ERα of the of the ERRγ the coactivator of a is by the presence of the acid and determined by the of the in ERRγ of ERRγ does not form to that of the in ERα. of ERRγ study we the crystal structures of the ERRγ LBD to the antagonists or with the in the transcriptionally active Our that and is the rotation of the side chain of which upon ligand binding of the and with in the agonist a is dissociated from the LBD and coactivator binding is are in with results that of Phe-435 to in the of ERRγ in (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). 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Although observations from structural and the of in the of the coactivator observed in the crystal structures of the ERα LBD with and may be to the In to the of of ER in the presence of or antagonists been in as for the or receptor γ LBD Biol. 2003; PubMed Scopus Google Scholar). the of ligand binding the conformation of the ERRγ LBD and the of have not been in In the absence of the crystal structures insight into the conformational changes by and of the ERRγ LBD to the of do not significant conformational changes upon the of which slightly from the of the to of the ligand but only in the of the ERRγ and may have we do not in the of the from the LBD body. The and observed in the complexes to be and by or crystal rather with ligand that observed for the ERα D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), does not the coactivator of LBD in the ERRγ Because the of the is in receptors, differences in the amino acid may explain of ERα of which and the of in the coactivator in the and the L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In no is in of and the and may not of with the coactivator Therefore, the of from the LBD upon or binding to ERRγ rather the of the ICI the in of binding to ERRγ receptor as for complexes J. Gustafsson J.A. M. 2001; 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S. R. U. S. A. PubMed Scopus Google Scholar) or potential as for complexes 2002; PubMed Scopus Google to be in the of the ERRγ in crystal form 1 of the ERRγ acid (or a for the presence of acid is that the been from the E. expression in the human are to be in the of that the the and J. 1999; Google Scholar). acid with of from a the coactivator groove and, the crystal a that been observed for a the in of the LBD Moras D. D. PubMed Scopus Google Scholar). The of acid to the of the and the of the that may be that the ERRγ LBD will a of the of we do not any for the observed of acid with the ERRγ Although ERRγ to be in the small and the (13Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, S. M. J. PubMed Scopus Google Scholar, J. H. Mol. Endocrinol. PubMed Scopus Google Scholar, U. Borgmeyer U. Biochem. Biophys. Res. PubMed Scopus Google Scholar), the binding position of the acid the ERRγ is determined by the crystal and only with but not agonist LBD acid with the ERRγ apoLBD. of have been shown to bind and and but not or D. L. C. J.A. J. Giguère V. Dev. 2001; PubMed Scopus Google Scholar, D. Giguère V. Endocrinology. 2001; PubMed Scopus Google Scholar, Lee D. J. U. S. A. 2001; PubMed Scopus Google Scholar). The of the and complexes of the ERRγ and the ERα LBDs reveals small but significant differences in the architecture of the that explain ligand binding The slightly shifted binding position of and the small rotation of in the of ERRγ result from to the presence of in and, relative to a shifted position of Furthermore, the side chain of Phe-435 in the Importantly, in ERα can conformational changes to as or that into the cavity L. Gustafsson J.A. 1997; PubMed Scopus Google Scholar, D. L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In even into conformational of in favorable or are by results significant binding of to the ERRγ and ERRγ in (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). Together, observations suggest that synthetic which as into the ER are to bind to ERRγ (or ERR whereas synthetic 4-OHT, which do not completely the are potential ERR In a study M. L. K. S. Mol. Cancer Res. 2003; Google Scholar) and as ERR their binding to ERR The used a of the ERRα LBD the ERα LBD to the presence of a that can or with the agonist Our of the antagonist-bound ERRγ LBDs with the ERβ J. Gustafsson J.A. M. EMBO J. 1999; 18: PubMed Scopus Google Scholar) a the side chain of of ERRγ and and of not In small of the might the binding of which the of with the ERRγ or to and as antagonists. Because of the ERRα and the LBD, which are the ERRγ rather the ERα LBD, suggest very architecture of the not is for ERR of the and ligand-bound LBD of ERRα and will that the architecture of the is the ERRγ LBD crystal structures provide a to the design of antagonists. the of and ERRγ are and which form a in In these to and The and of and be in the design of or In ERRα the are and the small may of that the is in and ERRα Our ERRα LBD that the receptor does not bind to the side chain of to in and in ERRγ (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. Cell. 2002; 9: 303-313Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). and to Phe-435 in are to completely the ERRα In with ERRα upon of to Lee D. J. U. S. A. 2001; PubMed Scopus Google Scholar), whereas ERRγ no to (12Greschik H. Wurtz J.-M. Sanglier S. Bourguet W. van Dorsselaer A. Moras D. Renaud J.-P. Mol. 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Greschik et al. (Mon,) studied this question.
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