1mmk

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{{STRUCTURE_1mmk| PDB=1mmk | SCENE= }}
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==Crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase ((FeII)) complexed with tetrahydrobiopterin and thienylalanine==
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===Crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase ((FeII)) complexed with tetrahydrobiopterin and thienylalanine===
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<StructureSection load='1mmk' size='340' side='right' caption='[[1mmk]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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{{ABSTRACT_PUBMED_14568534}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1mmk]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MMK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1MMK FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TIH:BETA(2-THIENYL)ALANINE'>TIH</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1kw0|1kw0]], [[1mmt|1mmt]], [[1j8u|1j8u]], [[1j8t|1j8t]]</td></tr>
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<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PAH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1mmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mmk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1mmk RCSB], [http://www.ebi.ac.uk/pdbsum/1mmk PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/PH4H_HUMAN PH4H_HUMAN]] Defects in PAH are the cause of phenylketonuria (PKU) [MIM:[http://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:[http://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:[http://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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==Disease==
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== Evolutionary Conservation ==
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[[http://www.uniprot.org/uniprot/PH4H_HUMAN PH4H_HUMAN]] Defects in PAH are the cause of phenylketonuria (PKU) [MIM:[http://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:[http://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:[http://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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[[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/mm/1mmk_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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The crystal structures of the catalytic domain of human phenylalanine hydroxylase (hPheOH) in complex with the physiological cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) and the substrate analogues 3-(2-thienyl)-L-alanine (THA) or L-norleucine (NLE) have been determined at 2.0A resolution. The ternary THA complex confirms a previous 2.5A structure, and the ternary NLE complex shows that similar large conformational changes occur on binding of NLE as those observed for THA. Both structures demonstrate that substrate binding triggers structural changes throughout the entire protomer, including the displacement of Tyr138 from a surface position to a buried position at the active site, with a maximum displacement of 20.7A for its hydroxyl group. Two hinge-bending regions, centred at Leu197 and Asn223, act in consort upon substrate binding to create further large structural changes for parts of the C terminus. Thus, THA/L-Phe binding to the active site is likely to represent the epicentre of the global conformational changes observed in the full-length tetrameric enzyme. The carboxyl and amino groups of THA and NLE are positioned identically in the two structures, supporting the conclusion that these groups are of key importance in substrate binding, thus explaining the broad non-physiological substrate specificity observed for artificially activated forms of the enzyme. However, the specific activity with NLE as the substrate was only about 5% of that with THA, which is explained by the different affinities of binding and different catalytic turnover.
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==About this Structure==
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2.0A resolution crystal structures of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine: substrate specificity and molecular motions related to substrate binding.,Andersen OA, Stokka AJ, Flatmark T, Hough E J Mol Biol. 2003 Oct 31;333(4):747-57. PMID:14568534<ref>PMID:14568534</ref>
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[[1mmk]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MMK OCA].
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
==See Also==
==See Also==
*[[Phenylalanine hydroxylase|Phenylalanine hydroxylase]]
*[[Phenylalanine hydroxylase|Phenylalanine hydroxylase]]
*[[Tryptophan hydroxylase 1 with bound tryptophan|Tryptophan hydroxylase 1 with bound tryptophan]]
*[[Tryptophan hydroxylase 1 with bound tryptophan|Tryptophan hydroxylase 1 with bound tryptophan]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:014568534</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Phenylalanine 4-monooxygenase]]
[[Category: Phenylalanine 4-monooxygenase]]

Revision as of 16:53, 29 September 2014

Crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase ((FeII)) complexed with tetrahydrobiopterin and thienylalanine

1mmk, resolution 2.00Å

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