Complex of human PXR with hyperforin Background: Treatment of illness with drugs is highly dependent on experience, which accumulated in the medical profession since ancient times. Plant extracts are substituted by semi- or fully synthetic substances, since function-structure relationships emerge to be understood. Still the simultaneous application of several drugs turns out to be complicated or harmful. So hyperforin, a traditionally used mild antidepressant from St. John's wort, may severely reduce the efficiency of other medication. The mechanism of this interference was revealed with the structure of a complex of hyperforin with a nuclear xenobiotic receptor. for freaks of chemical nomenclature: 4-hydroxy- 5-isobutyryl- 6-methyl- 1,3,7-tris- (3-methyl-but-2-enyl) -6-(4-methyl-pent-3-enyl) -bicyclo[3.3.1]non- 3-ene- 2,9-dione Chemical stress by xenobiotics is met in our body by the induction of metabolizing or excreting enzymes. One key inducer is pregnane X receptor (PXR), a ligand-activated transcription factor. It was shown that (among other substances) hyperforin is an activator of PXR. A direct involvement was demonstrated by cocrystallizing hyperforin with the ligand binding domain (LBD) of PXR. Structure of PXR-ligand binding domain: A common feature as found in other nuclear receptor LBDs is an alpha-helical sandwich of three layers: helices 1 and 3 (note a gap in the model between helix 1 and helix 2 due to disordered amino acids) helices 4, 5 and 8 helices 7 and 10 A five-stranded antiparallel sheet shields the ligand-binding cavity to one side (in other LBDs a three-stranded sheet is found instaed). Binding of the ligand: Hyperforin is held in the receptor by numerous contacts. Each of it's lipophilic tentacles (i.e. isoprenic sidechains) is held by a set of hydrophobic amino acids . Oxygen atoms of the drug are held by hydrogen bridges . Two fixed water molecules are in binding distance to hyperforin, too . Upon insertion of hyperforin the binding cavity of PXR is somewhat widened, as seen in comparison with the apo form of the receptor (marked magenta). In spite of the tight grip of the binding amino acids (yellow) there are in the protein channels allowing solvent access to the ligand (use your mouse to turn the protein and have a look from all angles!). The protein model shown here lacks the aminoterminal 141 aminoacids of the whole receptor . How conformational changes upon binding ligands are transmitted from the LBD to the unknown part of the receptor awaits further studies. Restart this demonstration Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
for freaks of chemical nomenclature: 4-hydroxy- 5-isobutyryl- 6-methyl- 1,3,7-tris- (3-methyl-but-2-enyl) -6-(4-methyl-pent-3-enyl) -bicyclo[3.3.1]non- 3-ene- 2,9-dione Chemical stress by xenobiotics is met in our body by the induction of metabolizing or excreting enzymes. One key inducer is pregnane X receptor (PXR), a ligand-activated transcription factor. It was shown that (among other substances) hyperforin is an activator of PXR. A direct involvement was demonstrated by cocrystallizing hyperforin with the ligand binding domain (LBD) of PXR. Structure of PXR-ligand binding domain: A common feature as found in other nuclear receptor LBDs is an alpha-helical sandwich of three layers: helices 1 and 3 (note a gap in the model between helix 1 and helix 2 due to disordered amino acids) helices 4, 5 and 8 helices 7 and 10 A five-stranded antiparallel sheet shields the ligand-binding cavity to one side (in other LBDs a three-stranded sheet is found instaed). Binding of the ligand: Hyperforin is held in the receptor by numerous contacts. Each of it's lipophilic tentacles (i.e. isoprenic sidechains) is held by a set of hydrophobic amino acids . Oxygen atoms of the drug are held by hydrogen bridges . Two fixed water molecules are in binding distance to hyperforin, too . Upon insertion of hyperforin the binding cavity of PXR is somewhat widened, as seen in comparison with the apo form of the receptor (marked magenta). In spite of the tight grip of the binding amino acids (yellow) there are in the protein channels allowing solvent access to the ligand (use your mouse to turn the protein and have a look from all angles!). The protein model shown here lacks the aminoterminal 141 aminoacids of the whole receptor . How conformational changes upon binding ligands are transmitted from the LBD to the unknown part of the receptor awaits further studies. Restart this demonstration Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
Chemical stress by xenobiotics is met in our body by the induction of metabolizing or excreting enzymes. One key inducer is pregnane X receptor (PXR), a ligand-activated transcription factor. It was shown that (among other substances) hyperforin is an activator of PXR. A direct involvement was demonstrated by cocrystallizing hyperforin with the ligand binding domain (LBD) of PXR. Structure of PXR-ligand binding domain: A common feature as found in other nuclear receptor LBDs is an alpha-helical sandwich of three layers: helices 1 and 3 (note a gap in the model between helix 1 and helix 2 due to disordered amino acids) helices 4, 5 and 8 helices 7 and 10 A five-stranded antiparallel sheet shields the ligand-binding cavity to one side (in other LBDs a three-stranded sheet is found instaed). Binding of the ligand: Hyperforin is held in the receptor by numerous contacts. Each of it's lipophilic tentacles (i.e. isoprenic sidechains) is held by a set of hydrophobic amino acids . Oxygen atoms of the drug are held by hydrogen bridges . Two fixed water molecules are in binding distance to hyperforin, too . Upon insertion of hyperforin the binding cavity of PXR is somewhat widened, as seen in comparison with the apo form of the receptor (marked magenta). In spite of the tight grip of the binding amino acids (yellow) there are in the protein channels allowing solvent access to the ligand (use your mouse to turn the protein and have a look from all angles!). The protein model shown here lacks the aminoterminal 141 aminoacids of the whole receptor . How conformational changes upon binding ligands are transmitted from the LBD to the unknown part of the receptor awaits further studies. Restart this demonstration Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
Structure of PXR-ligand binding domain: A common feature as found in other nuclear receptor LBDs is an alpha-helical sandwich of three layers: helices 1 and 3 (note a gap in the model between helix 1 and helix 2 due to disordered amino acids) helices 4, 5 and 8 helices 7 and 10 A five-stranded antiparallel sheet shields the ligand-binding cavity to one side (in other LBDs a three-stranded sheet is found instaed). Binding of the ligand: Hyperforin is held in the receptor by numerous contacts. Each of it's lipophilic tentacles (i.e. isoprenic sidechains) is held by a set of hydrophobic amino acids . Oxygen atoms of the drug are held by hydrogen bridges . Two fixed water molecules are in binding distance to hyperforin, too . Upon insertion of hyperforin the binding cavity of PXR is somewhat widened, as seen in comparison with the apo form of the receptor (marked magenta). In spite of the tight grip of the binding amino acids (yellow) there are in the protein channels allowing solvent access to the ligand (use your mouse to turn the protein and have a look from all angles!). The protein model shown here lacks the aminoterminal 141 aminoacids of the whole receptor . How conformational changes upon binding ligands are transmitted from the LBD to the unknown part of the receptor awaits further studies. Restart this demonstration Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
helices 1 and 3 (note a gap in the model between helix 1 and helix 2 due to disordered amino acids) helices 4, 5 and 8 helices 7 and 10
Binding of the ligand: Hyperforin is held in the receptor by numerous contacts. Each of it's lipophilic tentacles (i.e. isoprenic sidechains) is held by a set of hydrophobic amino acids . Oxygen atoms of the drug are held by hydrogen bridges . Two fixed water molecules are in binding distance to hyperforin, too . Upon insertion of hyperforin the binding cavity of PXR is somewhat widened, as seen in comparison with the apo form of the receptor (marked magenta). In spite of the tight grip of the binding amino acids (yellow) there are in the protein channels allowing solvent access to the ligand (use your mouse to turn the protein and have a look from all angles!). The protein model shown here lacks the aminoterminal 141 aminoacids of the whole receptor . How conformational changes upon binding ligands are transmitted from the LBD to the unknown part of the receptor awaits further studies. Restart this demonstration Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
The protein model shown here lacks the aminoterminal 141 aminoacids of the whole receptor . How conformational changes upon binding ligands are transmitted from the LBD to the unknown part of the receptor awaits further studies. Restart this demonstration Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
Restart this demonstration Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
Literature: RE Watkins et al, 2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin, Biochemistry 42 (2003) 1430-1438 6-03 - Rolf Bergmann
6-03 - Rolf Bergmann
