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7mk8

From Proteopedia

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Current revision

Crystal structure of a surface mutant of human fetal-specific CYP3A7 bound to dithiothreitol

Structural highlights

7mk8 is a 2 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 2.15Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CP3A7_HUMAN A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins during embryogenesis (PubMed:9555064, PubMed:11093772, PubMed:14559847, PubMed:12865317, PubMed:17178770). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:9555064, PubMed:11093772, PubMed:14559847, PubMed:12865317, PubMed:17178770). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA), a precursor in the biosynthesis of androgen and estrogen steroid hormones (PubMed:9555064, PubMed:17178770). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1), particularly D-ring hydroxylated estrone at the C16-alpha position (PubMed:14559847, PubMed:12865317). Mainly hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in atRA clearance during fetal development (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics including anticonvulsants (PubMed:9555064).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Cytochrome P450 3A7 (CYP3A7) is a fetal/neonatal liver enzyme that participates in estriol synthesis, clearance of all-trans retinoic acid, and xenobiotic metabolism. Compared to the closely related major drug-metabolizing enzyme in adult liver, CYP3A4, the ligand binding and catalytic capacity of CYP3A7 are substantially reduced. To better understand the structural basis for these functional differences, the 2.15 A crystal structure of CYP3A7 has been solved. Comparative analysis of CYP3A enzymes shows that decreased structural plasticity rather than the active site microenvironment defines the ligand binding ability of CYP3A7. In particular, a rotameric switch in the gatekeeping amino acid F304 triggers local and long-range rearrangements that transmit to the F-G fragment and alter its interactions with the I-E-D-helical core, resulting in a more rigid structure. Elongation of the beta3-beta4 strands, H-bond linkage in the substrate channel, and steric constraints in the C-terminal loop further increase the active site rigidity and limit conformational ensemble. Collectively, these structural distinctions lower protein plasticity and change the heme environment, which, in turn, could impede the spin-state transition essential for optimal reactivity and oxidation of substrates.

Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7.,Sevrioukova IF Int J Mol Sci. 2021 May 29;22(11). pii: ijms22115831. doi: 10.3390/ijms22115831. PMID:34072457^[6]

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

References

↑ Marill J, Cresteil T, Lanotte M, Chabot GG. Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol. 2000 Dec;58(6):1341-8. PMID:11093772 doi:10.1124/mol.58.6.1341
↑ Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98. PMID:12865317 doi:10.1210/en.2003-0192
↑ Lee AJ, Conney AH, Zhu BT. Human cytochrome P450 3A7 has a distinct high catalytic activity for the 16alpha-hydroxylation of estrone but not 17beta-estradiol. Cancer Res. 2003 Oct 1;63(19):6532-6 PMID:14559847
↑ Torimoto N, Ishii I, Toyama K, Hata M, Tanaka K, Shimomura H, Nakamura H, Ariyoshi N, Ohmori S, Kitada M. Helices F-G are important for the substrate specificities of CYP3A7. Drug Metab Dispos. 2007 Mar;35(3):484-92. PMID:17178770 doi:10.1124/dmd.106.011304
↑ Ohmori S, Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M. Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells. Biochim Biophys Acta. 1998 May 8;1380(3):297-304. PMID:9555064 doi:10.1016/s0304-4165(97)00156-6
↑ Sevrioukova IF. Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7. Int J Mol Sci. 2021 May 29;22(11). pii: ijms22115831. doi: 10.3390/ijms22115831. PMID:34072457 doi:http://dx.doi.org/10.3390/ijms22115831

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7mk8"

Categories: Homo sapiens | Large Structures | Sevrioukova IF

@@ Line 3: / Line 3: @@
 <StructureSection load='7mk8' size='340' side='right'caption='[[7mk8]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7mk8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MK8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MK8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7mk8]] is a 2 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=7MK8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MK8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTV:(2S,3S)-1,4-DIMERCAPTOBUTANE-2,3-DIOL'>DTV</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.15&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A7 ([https://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=DTV:(2S,3S)-1,4-DIMERCAPTOBUTANE-2,3-DIOL'>DTV</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7mk8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mk8 OCA], [https://pdbe.org/7mk8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mk8 RCSB], [https://www.ebi.ac.uk/pdbsum/7mk8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mk8 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/CP3A7_HUMAN CP3A7_HUMAN] A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins during embryogenesis (PubMed:9555064, PubMed:11093772, PubMed:14559847, PubMed:12865317, PubMed:17178770). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:9555064, PubMed:11093772, PubMed:14559847, PubMed:12865317, PubMed:17178770). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA), a precursor in the biosynthesis of androgen and estrogen steroid hormones (PubMed:9555064, PubMed:17178770). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1), particularly D-ring hydroxylated estrone at the C16-alpha position (PubMed:14559847, PubMed:12865317). Mainly hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in atRA clearance during fetal development (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics including anticonvulsants (PubMed:9555064).<ref>PMID:11093772</ref> <ref>PMID:12865317</ref> <ref>PMID:14559847</ref> <ref>PMID:17178770</ref> <ref>PMID:9555064</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 7mk8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Unspecific monooxygenase]]
+[[Category: Sevrioukova IF]]
-[[Category: Sevrioukova, I F]]
-[[Category: Cyp3a7]]
-[[Category: Cytochrome p450]]
-[[Category: Dithiothreitol]]
-[[Category: Oxidoreductase]]
-[[Category: Surface mutation]]

7mk8

From Proteopedia

Current revision

Crystal structure of a surface mutant of human fetal-specific CYP3A7 bound to dithiothreitol

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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