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| | ==Crystal structure analysis of the 2-enoyl-CoA hydratase 2 domain of human peroxisomal multifunctional enzyme type 2== | | ==Crystal structure analysis of the 2-enoyl-CoA hydratase 2 domain of human peroxisomal multifunctional enzyme type 2== |
| - | <StructureSection load='1s9c' size='340' side='right' caption='[[1s9c]], [[Resolution|resolution]] 3.00Å' scene=''> | + | <StructureSection load='1s9c' size='340' side='right'caption='[[1s9c]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1s9c]] is a 12 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=1S9C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1S9C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1s9c]] is a 12 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=1S9C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1S9C FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pn2|1pn2]], [[1pn4|1pn4]]</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]] 3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSD17B4, EDH17B4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=1s9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s9c OCA], [https://pdbe.org/1s9c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1s9c RCSB], [https://www.ebi.ac.uk/pdbsum/1s9c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1s9c 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=1s9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s9c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1s9c RCSB], [http://www.ebi.ac.uk/pdbsum/1s9c PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/DHB4_HUMAN DHB4_HUMAN]] Defects in HSD17B4 are a cause of D-bifunctional protein deficiency (DBPD) [MIM:[http://omim.org/entry/261515 261515]]. DBPD is a disorder of peroxisomal fatty acid beta-oxidation.<ref>PMID:9482850</ref> <ref>PMID:10400999</ref> <ref>PMID:11743515</ref> Defects in HSD17B4 are the cause of Perrault syndrome (PRLTS1) [MIM:[http://omim.org/entry/233400 233400]]. A sex-influenced disorder characterized by sensorineural deafness in both males and females and ovarian dysgenesis in females. Some patients also have neurologic manifestations, including mild mental retardation and cerebellar and peripheral nervous system involvement.<ref>PMID:20673864</ref> | + | [https://www.uniprot.org/uniprot/DHB4_HUMAN DHB4_HUMAN] Defects in HSD17B4 are a cause of D-bifunctional protein deficiency (DBPD) [MIM:[https://omim.org/entry/261515 261515]. DBPD is a disorder of peroxisomal fatty acid beta-oxidation.<ref>PMID:9482850</ref> <ref>PMID:10400999</ref> <ref>PMID:11743515</ref> Defects in HSD17B4 are the cause of Perrault syndrome (PRLTS1) [MIM:[https://omim.org/entry/233400 233400]. A sex-influenced disorder characterized by sensorineural deafness in both males and females and ovarian dysgenesis in females. Some patients also have neurologic manifestations, including mild mental retardation and cerebellar and peripheral nervous system involvement.<ref>PMID:20673864</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DHB4_HUMAN DHB4_HUMAN]] Bifunctional enzyme acting on the peroxisomal beta-oxidation pathway for fatty acids. Catalyzes the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids.<ref>PMID:9089413</ref> <ref>PMID:8902629</ref> | + | [https://www.uniprot.org/uniprot/DHB4_HUMAN DHB4_HUMAN] Bifunctional enzyme acting on the peroxisomal beta-oxidation pathway for fatty acids. Catalyzes the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids.<ref>PMID:9089413</ref> <ref>PMID:8902629</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/s9/1s9c_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/s9/1s9c_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </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]. | + | </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=1s9c ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 1s9c" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Hydroxysteroid dehydrogenase|Hydroxysteroid dehydrogenase]] | + | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Glumoff, T]] | + | [[Category: Large Structures]] |
| - | [[Category: Haapalainen, A M]] | + | [[Category: Glumoff T]] |
| - | [[Category: Hiltunen, J K]] | + | [[Category: Haapalainen AM]] |
| - | [[Category: Koski, M K]] | + | [[Category: Hiltunen JK]] |
| - | [[Category: Hot-dog fold]] | + | [[Category: Koski MK]] |
| - | [[Category: Hydratase 2 motif]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Multifunctional]]
| + | |
| Structural highlights
Disease
DHB4_HUMAN Defects in HSD17B4 are a cause of D-bifunctional protein deficiency (DBPD) [MIM:261515. DBPD is a disorder of peroxisomal fatty acid beta-oxidation.[1] [2] [3] Defects in HSD17B4 are the cause of Perrault syndrome (PRLTS1) [MIM:233400. A sex-influenced disorder characterized by sensorineural deafness in both males and females and ovarian dysgenesis in females. Some patients also have neurologic manifestations, including mild mental retardation and cerebellar and peripheral nervous system involvement.[4]
Function
DHB4_HUMAN Bifunctional enzyme acting on the peroxisomal beta-oxidation pathway for fatty acids. Catalyzes the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids.[5] [6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
2-Enoyl-CoA hydratase 2 is the middle part of the mammalian peroxisomal multifunctional enzyme type 2 (MFE-2), which is known to be important in the beta-oxidation of very-long-chain and alpha-methyl-branched fatty acids as well as in the synthesis of bile acids. Here, we present the crystal structure of the hydratase 2 from the human MFE-2 to 3A resolution. The three-dimensional structure resembles the recently solved crystal structure of hydratase 2 from the yeast, Candida tropicalis, MFE-2 having a two-domain subunit structure with a C-domain complete hot-dog fold housing the active site, and an N-domain incomplete hot-dog fold housing the cavity for the aliphatic acyl part of the substrate molecule. The ability of human hydratase 2 to utilize such bulky compounds which are not physiological substrates for the fungal ortholog, e.g. CoA esters of C26 fatty acids, pristanic acid and di/trihydroxycholestanoic acids, is explained by a large hydrophobic cavity formed upon the movements of the extremely mobile loops I-III in the N-domain. In the unliganded form of human hydratase 2, however, the loop I blocks the entrance of fatty enoyl-CoAs with chain-length >C8. Therefore, we expect that upon binding of substrates bulkier than C8, the loop I gives way, contemporaneously causing a secondary effect in the CoA-binding pocket and/or active site required for efficient hydration reaction. This structural feature would explain the inactivity of human hydratase 2 towards short-chain substrates. The solved structure is also used as a tool for analyzing the various inactivating mutations, identified among others in MFE-2-deficient patients. Since hydratase 2 is the last functional unit of mammalian MFE-2 whose structure has been solved, the organization of the functional units in the biologically active full-length enzyme is also discussed.
Crystal structure of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme type 2.,Koski KM, Haapalainen AM, Hiltunen JK, Glumoff T J Mol Biol. 2005 Feb 4;345(5):1157-69. Epub 2004 Dec 10. PMID:15644212[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ van Grunsven EG, van Berkel E, Ijlst L, Vreken P, de Klerk JB, Adamski J, Lemonde H, Clayton PT, Cuebas DA, Wanders RJ. Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2128-33. PMID:9482850
- ↑ van Grunsven EG, Mooijer PA, Aubourg P, Wanders RJ. Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional protein deficiency. Hum Mol Genet. 1999 Aug;8(8):1509-16. PMID:10400999
- ↑ Nakano K, Zhang Z, Shimozawa N, Kondo N, Ishii N, Funatsuka M, Shirakawa S, Itoh M, Takashima S, Une M, Kana-aki RR, Mukai K, Osawa M, Suzuki Y. D-bifunctional protein deficiency with fetal ascites, polyhydramnios, and contractures of hands and toes. J Pediatr. 2001 Dec;139(6):865-7. PMID:11743515 doi:10.1067/mpd.2001.119170
- ↑ Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet. 2010 Aug 13;87(2):282-8. doi: 10.1016/j.ajhg.2010.07.007. Epub, 2010 Jul 30. PMID:20673864 doi:10.1016/j.ajhg.2010.07.007
- ↑ Jiang LL, Miyazawa S, Souri M, Hashimoto T. Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein. J Biochem. 1997 Feb;121(2):364-9. PMID:9089413
- ↑ Jiang LL, Kobayashi A, Matsuura H, Fukushima H, Hashimoto T. Purification and properties of human D-3-hydroxyacyl-CoA dehydratase: medium-chain enoyl-CoA hydratase is D-3-hydroxyacyl-CoA dehydratase. J Biochem. 1996 Sep;120(3):624-32. PMID:8902629
- ↑ Koski KM, Haapalainen AM, Hiltunen JK, Glumoff T. Crystal structure of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme type 2. J Mol Biol. 2005 Feb 4;345(5):1157-69. Epub 2004 Dec 10. PMID:15644212 doi:10.1016/j.jmb.2004.11.009
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