- Email: [email protected]
Couple Dynamics: PPARγ and Its Ligand Partners
Structure
Previews influences on isotopic, organic, and inorganic chemical signatures in rocks, while powerful, are potentially subject to the influence of diagenetic processes and assumptions about ancient biochemistries (Fischer et al., 2005). The genome-based analyses, such as the application of conserved protein folding domains used by Kim et al. (2012), offer an important new tool in constraining this Proterozoic oceanscape. Yet, with these technical advances also comes a new challenge: the building of bridges across the cultural and scientific divides between biochemists and geochemists in order to further explore the co-evolution of life and biogeochemistry throughout Earth’s history.
from the National Science Foundation Chemical Oceanography and the Gordon and Betty Moore Foundation.
ACKNOWLEDGMENTS
Fischer, W.W., Summons, R.E., and Pearson, A. (2005). Geobiology 3, 33–40.
The author is grateful to Ariel Anbar and Chris Dupont for helpful comments. Funding support was
Kim, K.M., Qin, T., Jiang, Y.-Y., Chen, L.-L., Xiong, M., Caetano-Anolle´s, D., Zhang, H.-Y., and Cae-
REFERENCES Anbar, A.D., and Knoll, A.H. (2002). Science 297, 1137–1142. Canfield, D.E. (1998). Nature 396, 450–453. Canfield, D.E., Poulton, S.W., Knoll, A.H., Narbonne, G.M., Ross, G., Goldberg, T., and Strauss, H. (2008). Science 321, 949–952. Dupont, C.L., Butcher, A., Valas, R.E., Bourne, P.E., and Caetano-Anolle´s, G. (2010). Proc. Natl. Acad. Sci. USA 107, 10567–10572. Ettwig, K.F., Butler, M.K., Le Paslier, D., Pelletier, E., Mangenot, S., Kuypers, M.M.M., Schreiber, F., Dutilh, B.E., Zedelius, J., de Beer, D., et al. (2010). Nature 464, 543–548.
tano-Anolle´s, G. (2012). Structure 20, this issue, 67–76. Planavsky, N.J., McGoldrick, P., Scott, C.T., Li, C., Reinhard, C.T., Kelly, A.E., Chu, X., Bekker, A., Love, G.D., and Lyons, T.W. (2011). Nature 447, 448–451. Poulton, S.W., and Canfield, D.E. (2011). Elements 7, 107–112. Rouxel, O.J., Bekker, A., and Edwards, K.J. (2005). Science 307, 1088–1091. Saito, M.A., Moffett, J.W., Chisholm, S.W., and Waterbury, J.B. (2002). Limnol. Oceanogr. 47, 1629–1636. Saito, M.A., Sigman, D., and Morel, F.M.M. (2003). Inorganica Chim. Acta 356, 308–318. Summons, R.E., L.L. Jahnke, J.M. Hope, G.A. Logan. (1999). Nature. 5;400(6744):554-7. Wang, M., Jiang, Y.Y., Kim, K.M., Qu, G., Ji, H.F., Mittenthal, J.E., Zhang, H.Y., and CaetanoAnolle´s, G. (2011). Mol. Biol. Evol. 28, 567–582.
Couple Dynamics: PPARg and Its Ligand Partners Shanghai Yu1 and H. Eric Xu1,2,* 1VARI-SIMM Center, Center for Structure and Function of Drug Targets, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China 2Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, MI 49503, USA *Correspondence: [email protected] DOI 10.1016/j.str.2011.12.002
Ligand-regulated transcriptional activity is the most important property of nuclear receptors, including PPARg. In this issue of Structure, Hughes et al. determined how the dynamic conformations of ligands and the receptor contribute to the degree of ligand-dependent activation of PPARg, which provide further insights into design of PPARg-based anti-diabetic drugs. PPARg, a key activator of adipogenesis, is also the molecular target of the thiazolidinedione (TZD) class of anti-diabetic drugs such as rosiglitazone and pioglitazone. These TZD drugs are full agonists of PPARg that are able to promote adipocyte differentiation. Although TZDs improve insulin sensitivity and glucose metabolism, they have been associated with severe side effects including fluid retention, weight gain, and cardiovascular diseases. The major challenge of PPARg-based drug discovery is how to retain the beneficial glucose-lowering effects of PPARg ligands but avoid their -
undesired side effects. The attempts to overcome such challenges have been blocked by the lack of basic understanding of how PPARg activation by small molecule ligands is linked with their anti-diabetic effects. A series of recent papers, including the one by Hughes et al. (2012) in this issue of Structure, begin to shed light into complex mechanisms that link PPARg activity with insulin sensitivity and glucose metabolism. PPARg and two related receptors PPARa and PPARd/b comprise a subfamily of nuclear receptors, whose tran-
2 Structure 20, January 11, 2012 ª2012 Elsevier Ltd All rights reserved
scription activity is tightly controlled by the conformation of an activation helix (AF-2), which resides in the C terminus of the ligand binding domain. PPARg is known to have a ligand-independent basal activity (Xu and Li, 2008). As shown in Figure 1, in the absence of any ligand, the AF-2 helix of PPARg is in equilibrium between closed (active) and open (inactive) conformations (Nolte et al., 1998). The binding of activating ligands, such as TZD or fatty acids, locks the AF-2 in the active conformation through a tight interaction between the AF-2 helix and the bound ligand (Gampe et al., 2000;
Structure
Previews b sheet region of Ser-273, Nolte et al., 1998). In this AF-2 Apo thus blocking Cdk5 phosactive conformation, the AF-2 Apo flexible AF-2 phorylation. However, dechelix forms a charge-clamp PC PC β Ser-273 β Ser-273 anoic acid (DA), a 10-carbon pocket to interact with short fatty acid derived from natural LXXLL motifs of coactivators DA TZD middle chain-length triglycerthat are required for transcripstable ides, is a weak PPARg partial tional activation (Nolte et al., agonist that binds to the 1998). In contrast, the bindSer Ser thumb pocket (Figure 1). DA ing of antagonists, as seen does not stabilize PPARg, inin PPARa, destabilizes the cluding the b sheet and AF-2 AF-2 helix from the active MRL20 regions, thus it does not conformation and opens up Ser Ser inhibit Cdk5-mediated phosthe charge clamp pocket for phorylation of PPARg. Interbinding of larger LXXXIXXXL estingly, DA was able to immotifs of corepressors (Xu prove metabolism of glucose et al., 2002). For a long MRL24 and lipids without induction time, it was widely believed Ser Ser of adipogenesis and body that transcriptional activity weight gain (Malapaka et al., of PPARg by TZDs was 2011), suggesting complex responsible for TZD’s effects Figure 1. Dynamic Structures of PPARg in Apo and Various Ligandmechanisms of PPARg-medion insulin sensitivity and Bound States ated anti-diabetic effects glucose regulation as the Apo PPARg is shown with AF-2 helix, a hand-shaped ligand binding pocket (PC) and the b sheet (b) near Ser-273, with the AF-2 helix in a balance between beyond inhibition of Cdk5 in vitro affinity of PPARg open and closed conformations. The degree of Ser-273 phosphorylation is phosphorylation. correlate with the potency of shown with a red bar. Rosiglitazone (TZD) binding stabilizes the AF-2 and The paper by Hughes et al. their in vivo glucose lowering the b sheet, reducing Ser-273 phosphorylation, while DA does not have an effect on PPARg structure or Ser273-phosphorylation. MRL20 and MRL24 (2012) adds another layer of activity (Willson et al., 1996). adopt multiple conformations in the PPARg pocket with different stabilization complexity in PPARg-ligand This view is further supported of the AF-2 helix and the b sheet, thus affecting different levels of agonism and interactions. Through studies by recent evidence of adipoSer-273 phosphorylation. of NMR and hydrogen/deutecyte specific-knockout of rium exchange, the authors nuclear corepressor NCoR, which increases PPARg transcriptional Recent works from the Spiegelman discovered that AF-2 moves between all activity and improves glucose metabo- and Griffin groups, which reveal the link possible conformations on the intermelism (Li et al., 2011). of inhibition of Cdk5 phosphorylation of diate NMR exchange time scale and the However, the direct correlation PPARg by rosiglitazone and MRL24 degree of stabilization of the active AF-2 between PPARg transcriptional activity with their anti-diabetic effects, start to conformation by MRL24, MRL20, and roof ligands and their anti-diabetic effects provide answers to the third puzzle above siglitazone correlates with their agonist has been challenged from the very begin- (Choi et al., 2010). Cdk5 phosphorylates activity (Figure 1). The most unexpected ning. The first puzzle came from the PPARg at Ser-273. Both rosiglitazone discovery is the occurrence of the multiple genetic knockout PPARg in mice, where and MRL24 inhibit this phosphorylation bound conformations of MRL20 and heterozygous mice, which have half (MRL24 does not directly stabilize the MRL24 in the PPARg pocket, contradictactivity of wild-type, displayed more AF-2 helix), and this inhibition is corre- ing the single conformation observed in robust insulin sensitivity and glucose lated with its anti-diabetic outcome of the earlier crystal structures (Bruning metabolism than wild-type mice (Barak rosiglitazone in small clinical samples. et al., 2007). Correspondingly, the et al., 1999). Second, although specific Furthermore, SR1824, a non-agonist receptor also adopts multiple conformahigh affinity endogenous ligands have PPARg ligand that blocks Cdk5-mediated tions to accommodate the changes of not been identified (Xu and Li, 2008), fatty phosphorylation, has similar anti-diabetic ligand conformations. This observation acids are considered to be general effects as rosiglitazone, consistent with challenges the prevalent view of onePPARg ligands that are present in suffi- the fact that Cdk5-mediated phosphory- on-one ligand-receptor interactions with cient concentrations to activate PPARg lation may play a major role in the devel- respect to their bound conformations. in vivo (Xu et al., 1999). It is not clear opment of insulin resistance (Choi et al., The multiple docking modes arisen from why exogenous ligands would have 2011). However, blocking the Cdk5-medi- promiscuous coupling between ligand significant anti-diabetic effects. The final ated phosphorylation of PPARg may not and the receptor has also added sigpuzzle lies in several PPARg ligands, be the only path to develop PPARg-based nificant difficulties in structure-based including MRL24, which have very poor anti-diabetic drugs. PPARg has a large design of PPARg-based anti-diabetic agonist activities but have very good ligand binding pocket comprising of drugs. The continued quest for better anti-diabetic effects (Choi et al., 2010). a small hydrophobic thumb pocket and PPARg-based anti-diabetic drugs will These puzzles remain as the dark clouds a larger palm-like pocket (Figure 1). Both have to be rooted in the field of PPARg in the field of PPARg and diabetic rosiglitazone and MRL24 dock into the biology and pathology of diabetes, where research. larger palm pocket and stabilize the much remains to be learned. Structure 20, January 11, 2012 ª2012 Elsevier Ltd All rights reserved 3
Structure
Previews REFERENCES Barak, Y., Nelson, M.C., Ong, E.S., Jones, Y.Z., Ruiz-Lozano, P., Chien, K.R., Koder, A., and Evans, R.M. (1999). Mol. Cell 4, 585–595.
Gampe, R.T., Jr., Montana, V.G., Lambert, M.H., Miller, A.B., Bledsoe, R.K., Milburn, M.V., Kliewer, S.A., Willson, T.M., and Xu, H.E. (2000). Mol. Cell 5, 545–555.
Nolte, R.T., Wisely, G.B., Westin, S., Cobb, J.E., Lambert, M.H., Kurokawa, R., Rosenfeld, M.G., Willson, T.M., Glass, C.K., and Milburn, M.V. (1998). Nature 395, 137–143. Willson, T.M., Cobb, J.E., Cowan, D.J., Wiethe, R.W., Correa, I.D., Prakash, S.R., Beck, K.D., Moore, L.B., Kliewer, S.A., and Lehmann, J.M. (1996). J. Med. Chem. 39, 665–668.
Bruning, J.B., Chalmers, M.J., Prasad, S., Busby, S.A., Kamenecka, T.M., He, Y., Nettles, K.W., and Griffin, P.R. (2007). Structure 15, 1258–1271.
Hughes, T.S., Chalmers, M.J., Novick, S., Kuruvilla, D.S., Chang, M.R., Kamenecka, T.M., Rance, M., Johnson, B.A., Burris, T.P., Griffin, P.R., and Kojetin, D.J. (2012). Structure 20, this issue, 139–150.
Choi, J.H., Banks, A.S., Estall, J.L., Kajimura, S., Bostro¨m, P., Laznik, D., Ruas, J.L., Chalmers, M.J., Kamenecka, T.M., Blu¨her, M., et al. (2010). Nature 466, 451–456.
Li, P., Fan, W., Xu, J., Lu, M., Yamamoto, H., Auwerx, J., Sears, D.D., Talukdar, S., Oh, D., Chen, A., et al. (2011). Cell 147, 815–826.
Xu, H.E., Lambert, M.H., Montana, V.G., Parks, D.J., Blanchard, S.G., Brown, P.J., Sternbach, D.D., Lehmann, J.M., Wisely, G.B., Willson, T.M., et al. (1999). Mol. Cell 3, 397–403.
Choi, J.H., Banks, A.S., Kamenecka, T.M., Busby, S.A., Chalmers, M.J., Kumar, N., Kuruvilla, D.S., Shin, Y., He, Y., Bruning, J.B., et al. (2011). Nature 477, 477–481.
Malapaka, R.R.V., Khoo, S.K., Zhang, J., Choi, J.H., Zhou, X.E., Xu, Y., Gong, Y., Li, J., Yong, E., Chalmers, M.J., et al. (2011). J. Biol. Chem. 2011. 10.1074/jbc.M111.294785.
Xu, H.E., Stanley, T.B., Montana, V.G., Lambert, M.H., Shearer, B.G., Cobb, J.E., McKee, D.D., Galardi, C.M., Plunket, K.D., Nolte, R.T., et al. (2002). Nature 415, 813–817.
4 Structure 20, January 11, 2012 ª2012 Elsevier Ltd All rights reserved
Xu, H.E., and Li, Y. (2008). Sci. Signal. 1, pe52.
Previews influences on isotopic, organic, and inorganic chemical signatures in rocks, while powerful, are potentially subject to the influence of diagenetic processes and assumptions about ancient biochemistries (Fischer et al., 2005). The genome-based analyses, such as the application of conserved protein folding domains used by Kim et al. (2012), offer an important new tool in constraining this Proterozoic oceanscape. Yet, with these technical advances also comes a new challenge: the building of bridges across the cultural and scientific divides between biochemists and geochemists in order to further explore the co-evolution of life and biogeochemistry throughout Earth’s history.
from the National Science Foundation Chemical Oceanography and the Gordon and Betty Moore Foundation.
ACKNOWLEDGMENTS
Fischer, W.W., Summons, R.E., and Pearson, A. (2005). Geobiology 3, 33–40.
The author is grateful to Ariel Anbar and Chris Dupont for helpful comments. Funding support was
Kim, K.M., Qin, T., Jiang, Y.-Y., Chen, L.-L., Xiong, M., Caetano-Anolle´s, D., Zhang, H.-Y., and Cae-
REFERENCES Anbar, A.D., and Knoll, A.H. (2002). Science 297, 1137–1142. Canfield, D.E. (1998). Nature 396, 450–453. Canfield, D.E., Poulton, S.W., Knoll, A.H., Narbonne, G.M., Ross, G., Goldberg, T., and Strauss, H. (2008). Science 321, 949–952. Dupont, C.L., Butcher, A., Valas, R.E., Bourne, P.E., and Caetano-Anolle´s, G. (2010). Proc. Natl. Acad. Sci. USA 107, 10567–10572. Ettwig, K.F., Butler, M.K., Le Paslier, D., Pelletier, E., Mangenot, S., Kuypers, M.M.M., Schreiber, F., Dutilh, B.E., Zedelius, J., de Beer, D., et al. (2010). Nature 464, 543–548.
tano-Anolle´s, G. (2012). Structure 20, this issue, 67–76. Planavsky, N.J., McGoldrick, P., Scott, C.T., Li, C., Reinhard, C.T., Kelly, A.E., Chu, X., Bekker, A., Love, G.D., and Lyons, T.W. (2011). Nature 447, 448–451. Poulton, S.W., and Canfield, D.E. (2011). Elements 7, 107–112. Rouxel, O.J., Bekker, A., and Edwards, K.J. (2005). Science 307, 1088–1091. Saito, M.A., Moffett, J.W., Chisholm, S.W., and Waterbury, J.B. (2002). Limnol. Oceanogr. 47, 1629–1636. Saito, M.A., Sigman, D., and Morel, F.M.M. (2003). Inorganica Chim. Acta 356, 308–318. Summons, R.E., L.L. Jahnke, J.M. Hope, G.A. Logan. (1999). Nature. 5;400(6744):554-7. Wang, M., Jiang, Y.Y., Kim, K.M., Qu, G., Ji, H.F., Mittenthal, J.E., Zhang, H.Y., and CaetanoAnolle´s, G. (2011). Mol. Biol. Evol. 28, 567–582.
Couple Dynamics: PPARg and Its Ligand Partners Shanghai Yu1 and H. Eric Xu1,2,* 1VARI-SIMM Center, Center for Structure and Function of Drug Targets, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China 2Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, MI 49503, USA *Correspondence: [email protected] DOI 10.1016/j.str.2011.12.002
Ligand-regulated transcriptional activity is the most important property of nuclear receptors, including PPARg. In this issue of Structure, Hughes et al. determined how the dynamic conformations of ligands and the receptor contribute to the degree of ligand-dependent activation of PPARg, which provide further insights into design of PPARg-based anti-diabetic drugs. PPARg, a key activator of adipogenesis, is also the molecular target of the thiazolidinedione (TZD) class of anti-diabetic drugs such as rosiglitazone and pioglitazone. These TZD drugs are full agonists of PPARg that are able to promote adipocyte differentiation. Although TZDs improve insulin sensitivity and glucose metabolism, they have been associated with severe side effects including fluid retention, weight gain, and cardiovascular diseases. The major challenge of PPARg-based drug discovery is how to retain the beneficial glucose-lowering effects of PPARg ligands but avoid their -
undesired side effects. The attempts to overcome such challenges have been blocked by the lack of basic understanding of how PPARg activation by small molecule ligands is linked with their anti-diabetic effects. A series of recent papers, including the one by Hughes et al. (2012) in this issue of Structure, begin to shed light into complex mechanisms that link PPARg activity with insulin sensitivity and glucose metabolism. PPARg and two related receptors PPARa and PPARd/b comprise a subfamily of nuclear receptors, whose tran-
2 Structure 20, January 11, 2012 ª2012 Elsevier Ltd All rights reserved
scription activity is tightly controlled by the conformation of an activation helix (AF-2), which resides in the C terminus of the ligand binding domain. PPARg is known to have a ligand-independent basal activity (Xu and Li, 2008). As shown in Figure 1, in the absence of any ligand, the AF-2 helix of PPARg is in equilibrium between closed (active) and open (inactive) conformations (Nolte et al., 1998). The binding of activating ligands, such as TZD or fatty acids, locks the AF-2 in the active conformation through a tight interaction between the AF-2 helix and the bound ligand (Gampe et al., 2000;
Structure
Previews b sheet region of Ser-273, Nolte et al., 1998). In this AF-2 Apo thus blocking Cdk5 phosactive conformation, the AF-2 Apo flexible AF-2 phorylation. However, dechelix forms a charge-clamp PC PC β Ser-273 β Ser-273 anoic acid (DA), a 10-carbon pocket to interact with short fatty acid derived from natural LXXLL motifs of coactivators DA TZD middle chain-length triglycerthat are required for transcripstable ides, is a weak PPARg partial tional activation (Nolte et al., agonist that binds to the 1998). In contrast, the bindSer Ser thumb pocket (Figure 1). DA ing of antagonists, as seen does not stabilize PPARg, inin PPARa, destabilizes the cluding the b sheet and AF-2 AF-2 helix from the active MRL20 regions, thus it does not conformation and opens up Ser Ser inhibit Cdk5-mediated phosthe charge clamp pocket for phorylation of PPARg. Interbinding of larger LXXXIXXXL estingly, DA was able to immotifs of corepressors (Xu prove metabolism of glucose et al., 2002). For a long MRL24 and lipids without induction time, it was widely believed Ser Ser of adipogenesis and body that transcriptional activity weight gain (Malapaka et al., of PPARg by TZDs was 2011), suggesting complex responsible for TZD’s effects Figure 1. Dynamic Structures of PPARg in Apo and Various Ligandmechanisms of PPARg-medion insulin sensitivity and Bound States ated anti-diabetic effects glucose regulation as the Apo PPARg is shown with AF-2 helix, a hand-shaped ligand binding pocket (PC) and the b sheet (b) near Ser-273, with the AF-2 helix in a balance between beyond inhibition of Cdk5 in vitro affinity of PPARg open and closed conformations. The degree of Ser-273 phosphorylation is phosphorylation. correlate with the potency of shown with a red bar. Rosiglitazone (TZD) binding stabilizes the AF-2 and The paper by Hughes et al. their in vivo glucose lowering the b sheet, reducing Ser-273 phosphorylation, while DA does not have an effect on PPARg structure or Ser273-phosphorylation. MRL20 and MRL24 (2012) adds another layer of activity (Willson et al., 1996). adopt multiple conformations in the PPARg pocket with different stabilization complexity in PPARg-ligand This view is further supported of the AF-2 helix and the b sheet, thus affecting different levels of agonism and interactions. Through studies by recent evidence of adipoSer-273 phosphorylation. of NMR and hydrogen/deutecyte specific-knockout of rium exchange, the authors nuclear corepressor NCoR, which increases PPARg transcriptional Recent works from the Spiegelman discovered that AF-2 moves between all activity and improves glucose metabo- and Griffin groups, which reveal the link possible conformations on the intermelism (Li et al., 2011). of inhibition of Cdk5 phosphorylation of diate NMR exchange time scale and the However, the direct correlation PPARg by rosiglitazone and MRL24 degree of stabilization of the active AF-2 between PPARg transcriptional activity with their anti-diabetic effects, start to conformation by MRL24, MRL20, and roof ligands and their anti-diabetic effects provide answers to the third puzzle above siglitazone correlates with their agonist has been challenged from the very begin- (Choi et al., 2010). Cdk5 phosphorylates activity (Figure 1). The most unexpected ning. The first puzzle came from the PPARg at Ser-273. Both rosiglitazone discovery is the occurrence of the multiple genetic knockout PPARg in mice, where and MRL24 inhibit this phosphorylation bound conformations of MRL20 and heterozygous mice, which have half (MRL24 does not directly stabilize the MRL24 in the PPARg pocket, contradictactivity of wild-type, displayed more AF-2 helix), and this inhibition is corre- ing the single conformation observed in robust insulin sensitivity and glucose lated with its anti-diabetic outcome of the earlier crystal structures (Bruning metabolism than wild-type mice (Barak rosiglitazone in small clinical samples. et al., 2007). Correspondingly, the et al., 1999). Second, although specific Furthermore, SR1824, a non-agonist receptor also adopts multiple conformahigh affinity endogenous ligands have PPARg ligand that blocks Cdk5-mediated tions to accommodate the changes of not been identified (Xu and Li, 2008), fatty phosphorylation, has similar anti-diabetic ligand conformations. This observation acids are considered to be general effects as rosiglitazone, consistent with challenges the prevalent view of onePPARg ligands that are present in suffi- the fact that Cdk5-mediated phosphory- on-one ligand-receptor interactions with cient concentrations to activate PPARg lation may play a major role in the devel- respect to their bound conformations. in vivo (Xu et al., 1999). It is not clear opment of insulin resistance (Choi et al., The multiple docking modes arisen from why exogenous ligands would have 2011). However, blocking the Cdk5-medi- promiscuous coupling between ligand significant anti-diabetic effects. The final ated phosphorylation of PPARg may not and the receptor has also added sigpuzzle lies in several PPARg ligands, be the only path to develop PPARg-based nificant difficulties in structure-based including MRL24, which have very poor anti-diabetic drugs. PPARg has a large design of PPARg-based anti-diabetic agonist activities but have very good ligand binding pocket comprising of drugs. The continued quest for better anti-diabetic effects (Choi et al., 2010). a small hydrophobic thumb pocket and PPARg-based anti-diabetic drugs will These puzzles remain as the dark clouds a larger palm-like pocket (Figure 1). Both have to be rooted in the field of PPARg in the field of PPARg and diabetic rosiglitazone and MRL24 dock into the biology and pathology of diabetes, where research. larger palm pocket and stabilize the much remains to be learned. Structure 20, January 11, 2012 ª2012 Elsevier Ltd All rights reserved 3
Structure
Previews REFERENCES Barak, Y., Nelson, M.C., Ong, E.S., Jones, Y.Z., Ruiz-Lozano, P., Chien, K.R., Koder, A., and Evans, R.M. (1999). Mol. Cell 4, 585–595.
Gampe, R.T., Jr., Montana, V.G., Lambert, M.H., Miller, A.B., Bledsoe, R.K., Milburn, M.V., Kliewer, S.A., Willson, T.M., and Xu, H.E. (2000). Mol. Cell 5, 545–555.
Nolte, R.T., Wisely, G.B., Westin, S., Cobb, J.E., Lambert, M.H., Kurokawa, R., Rosenfeld, M.G., Willson, T.M., Glass, C.K., and Milburn, M.V. (1998). Nature 395, 137–143. Willson, T.M., Cobb, J.E., Cowan, D.J., Wiethe, R.W., Correa, I.D., Prakash, S.R., Beck, K.D., Moore, L.B., Kliewer, S.A., and Lehmann, J.M. (1996). J. Med. Chem. 39, 665–668.
Bruning, J.B., Chalmers, M.J., Prasad, S., Busby, S.A., Kamenecka, T.M., He, Y., Nettles, K.W., and Griffin, P.R. (2007). Structure 15, 1258–1271.
Hughes, T.S., Chalmers, M.J., Novick, S., Kuruvilla, D.S., Chang, M.R., Kamenecka, T.M., Rance, M., Johnson, B.A., Burris, T.P., Griffin, P.R., and Kojetin, D.J. (2012). Structure 20, this issue, 139–150.
Choi, J.H., Banks, A.S., Estall, J.L., Kajimura, S., Bostro¨m, P., Laznik, D., Ruas, J.L., Chalmers, M.J., Kamenecka, T.M., Blu¨her, M., et al. (2010). Nature 466, 451–456.
Li, P., Fan, W., Xu, J., Lu, M., Yamamoto, H., Auwerx, J., Sears, D.D., Talukdar, S., Oh, D., Chen, A., et al. (2011). Cell 147, 815–826.
Xu, H.E., Lambert, M.H., Montana, V.G., Parks, D.J., Blanchard, S.G., Brown, P.J., Sternbach, D.D., Lehmann, J.M., Wisely, G.B., Willson, T.M., et al. (1999). Mol. Cell 3, 397–403.
Choi, J.H., Banks, A.S., Kamenecka, T.M., Busby, S.A., Chalmers, M.J., Kumar, N., Kuruvilla, D.S., Shin, Y., He, Y., Bruning, J.B., et al. (2011). Nature 477, 477–481.
Malapaka, R.R.V., Khoo, S.K., Zhang, J., Choi, J.H., Zhou, X.E., Xu, Y., Gong, Y., Li, J., Yong, E., Chalmers, M.J., et al. (2011). J. Biol. Chem. 2011. 10.1074/jbc.M111.294785.
Xu, H.E., Stanley, T.B., Montana, V.G., Lambert, M.H., Shearer, B.G., Cobb, J.E., McKee, D.D., Galardi, C.M., Plunket, K.D., Nolte, R.T., et al. (2002). Nature 415, 813–817.
4 Structure 20, January 11, 2012 ª2012 Elsevier Ltd All rights reserved
Xu, H.E., and Li, Y. (2008). Sci. Signal. 1, pe52.