5hms: Difference between revisions
New page: ==X-ray structure of human recombinant 5-aminolaevulinic acid dehydratase (hrALAD).== <StructureSection load='5hms' size='340' side='right' caption='5hms, resolution 2.8... |
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==X-ray structure of human recombinant 5-aminolaevulinic acid dehydratase (hrALAD).== | ==X-ray structure of human recombinant 5-aminolaevulinic acid dehydratase (hrALAD).== | ||
<StructureSection load='5hms' size='340' side='right' caption='[[5hms]], [[Resolution|resolution]] 2.80Å' scene=''> | <StructureSection load='5hms' size='340' side='right'caption='[[5hms]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5hms]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HMS OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5hms]] 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=5HMS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HMS FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5hms FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hms OCA], [https://pdbe.org/5hms PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hms RCSB], [https://www.ebi.ac.uk/pdbsum/5hms PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hms ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/HEM2_HUMAN HEM2_HUMAN] Defects in ALAD are the cause of acute hepatic porphyria (AHEPP) [MIM:[https://omim.org/entry/612740 612740]. A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralysis, and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors.<ref>PMID:1569184</ref> <ref>PMID:2063868</ref> <ref>PMID:1309003</ref> <ref>PMID:10706561</ref> <ref>PMID:17236137</ref> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/HEM2_HUMAN HEM2_HUMAN] Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen.<ref>PMID:11032836</ref> <ref>PMID:19812033</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A number of X-ray analyses of an enzyme involved in a key early stage of tetrapyrrole biosynthesis are reported. Two structures of human 5-aminolaevulinate dehydratase (ALAD), native and recombinant, have been determined at 2.8 A resolution, showing that the enzyme adopts an octameric quaternary structure in accord with previously published analyses of the enzyme from a range of other species. However, this is in contrast to the finding that a disease-related F12L mutant of the human enzyme uniquely forms hexamers [Breinig et al. (2003), Nature Struct. Biol. 10, 757-763]. Monomers of all ALADs adopt the TIM-barrel fold; the subunit conformation that assembles into the octamer includes the N-terminal tail of one monomer curled around the (alpha/beta)8 barrel of a neighbouring monomer. Both crystal forms of the human enzyme possess two monomers per asymmetric unit, termed A and B. In the native enzyme there are a number of distinct structural differences between the A and B monomers, with the latter exhibiting greater disorder in a number of loop regions and in the active site. In contrast, the second monomer of the recombinant enzyme appears to be better defined and the active site of both monomers clearly possesses a zinc ion which is bound by three conserved cysteine residues. In native human ALAD, the A monomer also has a ligand resembling the substrate ALA which is covalently bound by a Schiff base to one of the active-site lysines (Lys252) and is held in place by an ordered active-site loop. In contrast, these features of the active-site structure are disordered or absent in the B subunit of the native human enzyme. The octameric structure of the zinc-dependent ALAD from the hyperthermophile Pyrobaculum calidifontis is also reported at a somewhat lower resolution of 3.5 A. Finally, the details are presented of a high-resolution structure of the Escherichia coli ALAD enzyme co-crystallized with a noncovalently bound moiety of the product, porphobilinogen (PBG). This structure reveals that the pyrrole side-chain amino group is datively bound to the active-site zinc ion and that the PBG carboxylates interact with the enzyme via hydrogen bonds and salt bridges with invariant residues. A number of hydrogen-bond interactions that were previously observed in the structure of yeast ALAD with a cyclic intermediate resembling the product PBG appear to be weaker in the new structure, suggesting that these interactions are only optimal in the transition state. | |||
Structural studies of substrate and product complexes of 5-aminolaevulinic acid dehydratase from humans, Escherichia coli and the hyperthermophile Pyrobaculum calidifontis.,Mills-Davies N, Butler D, Norton E, Thompson D, Sarwar M, Guo J, Gill R, Azim N, Coker A, Wood SP, Erskine PT, Coates L, Cooper JB, Rashid N, Akhtar M, Shoolingin-Jordan PM Acta Crystallogr D Struct Biol. 2017 Jan 1;73(Pt 1):9-21. doi:, 10.1107/S2059798316019525. Epub 2017 Jan 1. PMID:28045381<ref>PMID:28045381</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5hms" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Porphobilinogen synthase|Porphobilinogen synthase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Butler | [[Category: Large Structures]] | ||
[[Category: Cooper | [[Category: Butler D]] | ||
[[Category: Erskine | [[Category: Cooper JB]] | ||
[[Category: Shoolingin-Jordan | [[Category: Erskine PT]] | ||
[[Category: Shoolingin-Jordan PM]] | |||