6pah

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[[Image:6pah.gif|left|200px]]<br /><applet load="6pah" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="6pah, resolution 2.15&Aring;" />
 
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'''HUMAN PHENYLALANINE HYDROXYLASE CATALYTIC DOMAIN DIMER WITH BOUND L-DOPA (3,4-DIHYDROXYPHENYLALANINE) INHIBITOR'''<br />
 
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==Overview==
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==HUMAN PHENYLALANINE HYDROXYLASE CATALYTIC DOMAIN DIMER WITH BOUND L-DOPA (3,4-DIHYDROXYPHENYLALANINE) INHIBITOR==
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The aromatic amino acid hydroxylases represent a superfamily of, structurally and functionally closely related enzymes, one of those, functions being reversible inhibition by catechol derivatives. Here we, present the crystal structure of the dimeric catalytic domain (residues, 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with, various potent and well-known catechol inhibitors and refined at a, resolution of 2.0 A. The catechols bind by bidentate coordination to each, iron in both subunits of the dimer through the catechol hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In, addition, Glu330 and Tyr325 are identified as determinant residues in the, recognition of the inhibitors. In particular, the interaction with Glu330, conforms to the structural explanation for the pH dependence of, catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The, overall structure of the catechol-bound enzyme is very similar to that of, the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms)., Most striking is the replacement of two iron-bound water molecules with, catechol hydroxyl groups. This change is consistent with a change in the, ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to, a nearly axial ligand field symmetry as seen upon noradrenaline binding, using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and, Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic, comparison with the structurally related rat tyrosine hydroxylase binary, complex with the oxidized cofactor 7,8-dihydrobiopterin revealed, overlapping binding sites for the catechols and the cofactor, compatible, with a competitive type of inhibition of the catechols versus BH4. The, comparison demonstrates some structural differences at the active site as, the potential basis for the different substrate specificity of the two, enzymes.
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<StructureSection load='6pah' size='340' side='right'caption='[[6pah]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6pah]] 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=6PAH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PAH FirstGlance]. <br>
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</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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DAH:3,4-DIHYDROXYPHENYLALANINE'>DAH</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6pah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pah OCA], [https://pdbe.org/6pah PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pah RCSB], [https://www.ebi.ac.uk/pdbsum/6pah PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pah ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PH4H_HUMAN PH4H_HUMAN] Defects in PAH are the cause of phenylketonuria (PKU) [MIM:[https://omim.org/entry/261600 261600]. PKU is an autosomal recessive inborn error of phenylalanine metabolism, due to severe phenylalanine hydroxylase deficiency. It is characterized by blood concentrations of phenylalanine persistently above 1200 mumol (normal concentration 100 mumol) which usually causes mental retardation (unless low phenylalanine diet is introduced early in life). They tend to have light pigmentation, rashes similar to eczema, epilepsy, extreme hyperactivity, psychotic states and an unpleasant 'mousy' odor.<ref>PMID:8594560</ref> <ref>PMID:2840952</ref> <ref>PMID:2564729</ref> <ref>PMID:2615649</ref> <ref>PMID:1975559</ref> <ref>PMID:1671810</ref> <ref>PMID:2014802</ref> <ref>PMID:1672294</ref> <ref>PMID:1672290</ref> <ref>PMID:1679030</ref> <ref>PMID:1709636</ref> <ref>PMID:1355066</ref> <ref>PMID:1363837</ref> <ref>PMID:1363838</ref> <ref>PMID:8406445</ref> <ref>PMID:8068076</ref> <ref>PMID:7833954</ref> <ref>PMID:8889583</ref> <ref>PMID:8889590</ref> <ref>PMID:9048935</ref> <ref>PMID:9101291</ref> <ref>PMID:9521426</ref> <ref>PMID:9600453</ref> <ref>PMID:10200057</ref> <ref>PMID:9452061</ref> <ref>PMID:9452062</ref> <ref>PMID:9792407</ref> <ref>PMID:9792411</ref> <ref>PMID:9950317</ref> <ref>PMID:10679941</ref> <ref>PMID:11326337</ref> <ref>PMID:11180595</ref> <ref>PMID:11385716</ref> <ref>PMID:11461196</ref> <ref>PMID:12501224</ref> <ref>PMID:18538294</ref> <ref>PMID:22526846</ref> <ref>PMID:22513348</ref> Defects in PAH are the cause of non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:[https://omim.org/entry/261600 261600]. Non-PKU HPA is a mild form of phenylalanine hydroxylase deficiency characterized by phenylalanine levels persistently below 600 mumol, which allows normal intellectual and behavioral development without treatment. Non-PKU HPA is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe one. Defects in PAH are the cause of hyperphenylalaninemia (HPA) [MIM:[https://omim.org/entry/261600 261600]. HPA is the mildest form of phenylalanine hydroxylase deficiency.<ref>PMID:9521426</ref> <ref>PMID:11385716</ref> <ref>PMID:12501224</ref> <ref>PMID:1358789</ref> <ref>PMID:8098245</ref> <ref>PMID:8088845</ref> <ref>PMID:9852673</ref> <ref>PMID:11935335</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/PH4H_HUMAN PH4H_HUMAN]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pa/6pah_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=6pah ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Hyperphenylalaninemia, mild OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=261600 261600]], Phenylketonuria OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=261600 261600]]
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*[[Hydroxylases 3D structures|Hydroxylases 3D structures]]
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*[[Monooxygenase 3D structures|Monooxygenase 3D structures]]
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==About this Structure==
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== References ==
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6PAH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FE and DAH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Phenylalanine_4-monooxygenase Phenylalanine 4-monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.16.1 1.14.16.1] Known structural/functional Site: <scene name='pdbsite=NUL:Fe Binding Ligands'>NUL</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=6PAH OCA].
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<references/>
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__TOC__
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==Reference==
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</StructureSection>
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Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution., Erlandsen H, Flatmark T, Stevens RC, Hough E, Biochemistry. 1998 Nov 10;37(45):15638-46. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9843368 9843368]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Phenylalanine 4-monooxygenase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Erlandsen H]]
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[[Category: Erlandsen, H.]]
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[[Category: Flatmark T]]
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[[Category: Flatmark, T.]]
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[[Category: Stevens RC]]
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[[Category: Stevens, R.C.]]
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[[Category: DAH]]
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[[Category: FE]]
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[[Category: non-heme iron-containing monooxygenase]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 20:47:21 2007''
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Current revision

HUMAN PHENYLALANINE HYDROXYLASE CATALYTIC DOMAIN DIMER WITH BOUND L-DOPA (3,4-DIHYDROXYPHENYLALANINE) INHIBITOR

PDB ID 6pah

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