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7lad

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Clobetasol propionate bound to CYP3A5

Structural highlights

7lad is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.65Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CP3A5_HUMAN Tacrolimus dose selection.

Function

CP3A5_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 (CYP) CYP3A4 and CYP3A5 enzymes metabolize more than one-half of marketed drugs. They share high structural and substrate similarity and are often studied together as CYP3A4/5. However, CYP3A5 preferentially metabolizes several clinically prescribed drugs, such as tacrolimus. Genetic polymorphism in CYP3A5 makes race-based dosing adjustment of tacrolimus necessary to minimize acute rejection after organ transplantation. Moreover, the differential tissue distribution and expression levels of CYP3A4 and CYP3A5 can aggravate toxicity during treatment. Therefore, selective inhibitors of CYP3A5 are needed to distinguish the role of CYP3A5 from that of CYP3A4 and serve as starting points for potential therapeutic development. To this end, we report the crystal structure of CYP3A5 in complex with a previously reported selective inhibitor, clobetasol propionate (CBZ). This is the first CYP3A5 structure with a type I inhibitor, which along with the previously reported substrate-free and type II inhibitor-bound structures, constitute the main CYP3A5 structural modalities. Supported by structure-guided mutagenesis analyses, the CYP3A5-CBZ structure showed that a unique conformation of the F-F' loop in CYP3A5 enables selective binding of CBZ to CYP3A5. Several polar interactions, including hydrogen bonds, stabilize the position of CBZ to interact with this unique F-F' loop conformation. In addition, functional and biophysical assays using CBZ analogs highlight the importance of heme-adjacent moieties for selective CYP3A5 inhibition. Our findings can be used to guide further development of more potent and selective CYP3A5 inhibitors.

Unraveling the Structural Basis of Selective Inhibition of Human Cytochrome P450 3A5.,Wang J, Buchman CD, Seetharaman J, Miller DJ, Huber AD, Wu J, Chai SC, Garcia-Maldonado E, Wright WC, Chenge J, Chen T J Am Chem Soc. 2021 Oct 14. doi: 10.1021/jacs.1c07066. PMID:34648292^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang J, Buchman CD, Seetharaman J, Miller DJ, Huber AD, Wu J, Chai SC, Garcia-Maldonado E, Wright WC, Chenge J, Chen T. Unraveling the Structural Basis of Selective Inhibition of Human Cytochrome P450 3A5. J Am Chem Soc. 2021 Oct 14. doi: 10.1021/jacs.1c07066. PMID:34648292 doi:http://dx.doi.org/10.1021/jacs.1c07066

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7lad"

@@ Line 3: / Line 3: @@
 <StructureSection load='7lad' size='340' side='right'caption='[[7lad]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7lad]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LAD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LAD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7lad]] is a 1 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=7LAD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LAD FirstGlance]. <br>
-</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=XRD:Clobetasol+propionate'>XRD</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]] 2.65&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></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=XRD:Clobetasol+propionate'>XRD</scene></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=7lad FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lad OCA], [https://pdbe.org/7lad PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lad RCSB], [https://www.ebi.ac.uk/pdbsum/7lad PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lad ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/CP3A5_HUMAN CP3A5_HUMAN]] Tacrolimus dose selection.
+[https://www.uniprot.org/uniprot/CP3A5_HUMAN CP3A5_HUMAN] Tacrolimus dose selection.
 == Function ==
-[[https://www.uniprot.org/uniprot/CP3A5_HUMAN CP3A5_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/CP3A5_HUMAN CP3A5_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;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 7lad" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Unspecific monooxygenase]]
+[[Category: Buchman CD]]
-[[Category: Buchman, C D]]
+[[Category: Chen T]]
-[[Category: Chen, T]]
+[[Category: Jayaraman S]]
-[[Category: Jayaraman, S]]
+[[Category: Miller D]]
-[[Category: Miller, D]]
+[[Category: Wang J]]
-[[Category: Wang, J]]
-[[Category: Cyp3a5]]
-[[Category: Cytochrome p450]]
-[[Category: Membrane protein]]

7lad

From Proteopedia

Current revision

Clobetasol propionate bound to CYP3A5

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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