- Email: [email protected]
Alcohol addiction
448
News & Comment
TRENDS in Pharmacological Sciences Vol.22 No.9 September 2001
In Brief
genome; the race is now on to understand how these promoter regions are ‘marked’. In the meantime, we eagerly await the results of the next study to use this powerful genomic mapping approach to identify the in vivo binding sites of other transcription factors with unknown DNA binding specificities.
1 Lieb, J.D. et al. (2001) Promoter-specific binding of Rap1 revealed by genome-wide maps of protein-DNA association. Nat. Genet. (published online ahead of print)
Alcohol addiction
Marion MacFarlane [email protected]
The PXR ligand-binding domain: how to be picky and promiscuous at the same time The pregnane-X receptor (PXR) – or should that be ‘promiscuous xenobiotic receptor’ – has hit the headlines again. The PXR is the nuclear receptor that upregulates the body’s primary chemical defense system in response to challenge. In particular, PXR induces CYP3A4, a cytochrome P450 that has exceptional versatility in the substrates it can metabolize, and therefore potentially detoxify. Unfortunately, PXR-mediated induction of CYP3A4 leads to many adverse drug interactions, where one drug enhances the metabolism of another. PXR can be activated by a range of ligands that is almost as diverse as the substrates of CYP3A4, including many drugs [e.g. steroids (dexamethasone) and macrolide antibiotics (rifampicin)]; however, PXR can also display considerable discretion. Watkins et al.1 have now helped to rationalize this selective promiscuity by solving the structure of the ligand-binding domain (LBD) of the PXR in the presence and absence of a prototypical inducer, SR12813. PXR shares the same overall arrangement of its functional domains as other nuclear receptors, such as the vitamin D, estrogen and progesterone receptors, all of which tend to be specialized to bind discrete physiological ligands. The crystal structure confirms this homology at the structural level, but reveals why the PXR, in contrast to other nuclear receptors, can bind structurally diverse ligands. The PXR binding site appears to have a bit of everything! It is mostly hydrophobic, matching the typical lipophilicity of substrates and/or inducers of the CYP3A–PXR system. However, there are several evenly spaced polar residues towards one end that interact with SR12813. Most significantly perhaps, the PXR binding site is generally enlarged compared with related nuclear receptors, to fit larger and more varied ligands. In addition, there is a flexible loop that might be displaced http://tips.trends.com
by bulky ligands to allow access to an additional hydrophobic cavity. Several different binding orientations of SR12813 were apparent in the ligand-bound structure, and it is likely that the structurally diverse PXR ligands bind in very different ways, again in contrast to other nuclear receptors. Watkins et al. also showed that the inducer selectivity of PXR might be mediated by a few discrete structural elements. These authors were able to convert the selectivity of the mouse PXR to that of the human by mutating only four key residues. The unbound and SR12813-bound structures differed little in overall conformation, consistent perhaps with the fact that the PXR shows basal ligandindependent activity. However, it is unclear how ligand binding enhances activity or whether diverse ligands might bind in such a way as to exert subtle idiosyncratic, conformational effects on cofactor recruitment or other aspects of transcriptional activation, as has been demonstrated in the case of selective estrogen response modifiers and the estrogen receptor. The effects of binding of large ligands, which might access additional space in the LBD by displacing the flexible loop, will be particularly interesting in this regard. One thing is sure, given the clinical importance of PXR-mediated drug interactions, the changing temperament of the PXR is likely to tantalize structural biologists and toxicologists alike for some time yet. 1 Watkins, R.E. et al. (2001) The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292, 2329–2333
Elizabeth M.J. Gillam [email protected]
Two abstracts, presented at the British Pharmacological Society conference in July, shed light on alcohol addiction. Alcohol craving can be triggered by environmental stimuli. Barry Everitt and colleagues have been studying this process and have demonstrated that the so-called ‘emotional brain’ or limbic system is involved. Intriguingly, they have identified a dopamine D3 receptor partial agonist that diminishes cue-controlled drug seeking. Another factor in the development of alcohol dependence is binge drinking. Crews and colleagues, studying CNS alterations associated with binge drinking, found that binge drinking resulted in the induction of many genes, including Fos and Ptgs2. Because adolescent drinking is a particular risk factor for alcohol dependence, the importance of age was also evaluated. CNS changes were found to be greater in the younger rats compared with their older relatives. KP
Combating resistant TB The World Health Organization (WHO) has secured a deal with the manufacturers of the leading tuberculosis (TB) drugs with the hope of curbing the spread of the drug-resistant form of the disease. The producers of the drugs, which include Eli Lilly, have agreed to cut what they charge the WHO for drugs supplied to poor countries by 60–90%. Although only 1.5% of TB cases are drug resistant, this form of TB is escalating in some regions of Russia, Peru and the Philippines. This move by drug producers follows the industry’s recent U-turn over HIV drug patents in South Africa, but the new deal is conditional: the companies have warned they will pull out if the WHO is unable to enforce the strict dosing regimes that must be followed for the drugs to be effective. DC
0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
News & Comment
TRENDS in Pharmacological Sciences Vol.22 No.9 September 2001
In Brief
genome; the race is now on to understand how these promoter regions are ‘marked’. In the meantime, we eagerly await the results of the next study to use this powerful genomic mapping approach to identify the in vivo binding sites of other transcription factors with unknown DNA binding specificities.
1 Lieb, J.D. et al. (2001) Promoter-specific binding of Rap1 revealed by genome-wide maps of protein-DNA association. Nat. Genet. (published online ahead of print)
Alcohol addiction
Marion MacFarlane [email protected]
The PXR ligand-binding domain: how to be picky and promiscuous at the same time The pregnane-X receptor (PXR) – or should that be ‘promiscuous xenobiotic receptor’ – has hit the headlines again. The PXR is the nuclear receptor that upregulates the body’s primary chemical defense system in response to challenge. In particular, PXR induces CYP3A4, a cytochrome P450 that has exceptional versatility in the substrates it can metabolize, and therefore potentially detoxify. Unfortunately, PXR-mediated induction of CYP3A4 leads to many adverse drug interactions, where one drug enhances the metabolism of another. PXR can be activated by a range of ligands that is almost as diverse as the substrates of CYP3A4, including many drugs [e.g. steroids (dexamethasone) and macrolide antibiotics (rifampicin)]; however, PXR can also display considerable discretion. Watkins et al.1 have now helped to rationalize this selective promiscuity by solving the structure of the ligand-binding domain (LBD) of the PXR in the presence and absence of a prototypical inducer, SR12813. PXR shares the same overall arrangement of its functional domains as other nuclear receptors, such as the vitamin D, estrogen and progesterone receptors, all of which tend to be specialized to bind discrete physiological ligands. The crystal structure confirms this homology at the structural level, but reveals why the PXR, in contrast to other nuclear receptors, can bind structurally diverse ligands. The PXR binding site appears to have a bit of everything! It is mostly hydrophobic, matching the typical lipophilicity of substrates and/or inducers of the CYP3A–PXR system. However, there are several evenly spaced polar residues towards one end that interact with SR12813. Most significantly perhaps, the PXR binding site is generally enlarged compared with related nuclear receptors, to fit larger and more varied ligands. In addition, there is a flexible loop that might be displaced http://tips.trends.com
by bulky ligands to allow access to an additional hydrophobic cavity. Several different binding orientations of SR12813 were apparent in the ligand-bound structure, and it is likely that the structurally diverse PXR ligands bind in very different ways, again in contrast to other nuclear receptors. Watkins et al. also showed that the inducer selectivity of PXR might be mediated by a few discrete structural elements. These authors were able to convert the selectivity of the mouse PXR to that of the human by mutating only four key residues. The unbound and SR12813-bound structures differed little in overall conformation, consistent perhaps with the fact that the PXR shows basal ligandindependent activity. However, it is unclear how ligand binding enhances activity or whether diverse ligands might bind in such a way as to exert subtle idiosyncratic, conformational effects on cofactor recruitment or other aspects of transcriptional activation, as has been demonstrated in the case of selective estrogen response modifiers and the estrogen receptor. The effects of binding of large ligands, which might access additional space in the LBD by displacing the flexible loop, will be particularly interesting in this regard. One thing is sure, given the clinical importance of PXR-mediated drug interactions, the changing temperament of the PXR is likely to tantalize structural biologists and toxicologists alike for some time yet. 1 Watkins, R.E. et al. (2001) The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292, 2329–2333
Elizabeth M.J. Gillam [email protected]
Two abstracts, presented at the British Pharmacological Society conference in July, shed light on alcohol addiction. Alcohol craving can be triggered by environmental stimuli. Barry Everitt and colleagues have been studying this process and have demonstrated that the so-called ‘emotional brain’ or limbic system is involved. Intriguingly, they have identified a dopamine D3 receptor partial agonist that diminishes cue-controlled drug seeking. Another factor in the development of alcohol dependence is binge drinking. Crews and colleagues, studying CNS alterations associated with binge drinking, found that binge drinking resulted in the induction of many genes, including Fos and Ptgs2. Because adolescent drinking is a particular risk factor for alcohol dependence, the importance of age was also evaluated. CNS changes were found to be greater in the younger rats compared with their older relatives. KP
Combating resistant TB The World Health Organization (WHO) has secured a deal with the manufacturers of the leading tuberculosis (TB) drugs with the hope of curbing the spread of the drug-resistant form of the disease. The producers of the drugs, which include Eli Lilly, have agreed to cut what they charge the WHO for drugs supplied to poor countries by 60–90%. Although only 1.5% of TB cases are drug resistant, this form of TB is escalating in some regions of Russia, Peru and the Philippines. This move by drug producers follows the industry’s recent U-turn over HIV drug patents in South Africa, but the new deal is conditional: the companies have warned they will pull out if the WHO is unable to enforce the strict dosing regimes that must be followed for the drugs to be effective. DC
0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.