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| | <StructureSection load='6o5y' size='340' side='right'caption='[[6o5y]], [[Resolution|resolution]] 3.17Å' scene=''> | | <StructureSection load='6o5y' size='340' side='right'caption='[[6o5y]], [[Resolution|resolution]] 3.17Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6o5y]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O5Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O5Y FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6o5y]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O5Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O5Y FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=KUV:5-amino-N-{5-[(4R,5R)-4-amino-5-fluoroazepan-1-yl]-1-methyl-1H-pyrazol-4-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide'>KUV</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.17Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP1A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=KUV:5-amino-N-{5-[(4R,5R)-4-amino-5-fluoroazepan-1-yl]-1-methyl-1H-pyrazol-4-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide'>KUV</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6o5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o5y OCA], [https://pdbe.org/6o5y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o5y RCSB], [https://www.ebi.ac.uk/pdbsum/6o5y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o5y ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6o5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o5y OCA], [http://pdbe.org/6o5y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o5y RCSB], [http://www.ebi.ac.uk/pdbsum/6o5y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o5y ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP1A1_HUMAN CP1A1_HUMAN]] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. | + | [https://www.uniprot.org/uniprot/CP1A1_HUMAN CP1A1_HUMAN] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6o5y" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6o5y" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Unspecific monooxygenase]]
| + | [[Category: Bart AG]] |
| - | [[Category: Bart, A G]] | + | [[Category: Scott EE]] |
| - | [[Category: Scott, E E]] | + | |
| - | [[Category: Cyp1a1]]
| + | |
| - | [[Category: Gdc-0339]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: P450]]
| + | |
| Structural highlights
Function
CP1A1_HUMAN Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Publication Abstract from PubMed
The human cytochrome P450 1A1 (CYP1A1) is well-known for chemical activation of procarcinogens and often has a substrate scope towards small and highly planar compounds. Substrates deviating from these characteristics are certainly known, but how these larger and nonplanar substrates are accommodated and oriented within the CYP1A1 active site is not understood. Herein a new X-ray structure of CYP1A1 bound to the pan-Pim kinase inhibitor GDC-0339 reveals how the CYP1A1 active site cavity is reconfigured to bind larger and nonplanar compounds. The shape and size of the cavity are controlled by structural elements in the active site roof, with major changes in the conformation of the F helix break and relocation of Phe224 from the active site to the protein surface. This altered CYP1A1 active site architecture is consistent with the proposed mechanism for CYP1A1 generation of an unusual aminoazepane-rearranged metabolite for this substrate. SIGNIFICANCE STATEMENT: Cytochrome P450 1A1 metabolizes drugs, procarcinogens, and toxins and while previous structures have revealed how its stereotypical planar, aromatic compounds are accommodated in the CYP1A1 active site, this is not the case for flexible and nonplanar compounds. The current work determines the X-ray structure of CYP1A1 with such a flexible, nonplanar Pim kinase inhibitor, revealing significant modification of the CYP1A1 roof that accommodate this preclinical candidate and support an unusual intramolecular rearrangement reaction.
Human Cytochrome P450 1A1 Adapts Active Site for Atypical Nonplanar Substrate.,Bart AG, Takahashi RH, Wang X, Scott EE Drug Metab Dispos. 2019 Nov 22. pii: dmd.119.089607. doi: 10.1124/dmd.119.089607. PMID:31757797[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bart AG, Takahashi RH, Wang X, Scott EE. Human Cytochrome P450 1A1 Adapts Active Site for Atypical Nonplanar Substrate. Drug Metab Dispos. 2019 Nov 22. pii: dmd.119.089607. doi: 10.1124/dmd.119.089607. PMID:31757797 doi:http://dx.doi.org/10.1124/dmd.119.089607
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