3leo: Difference between revisions
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==Structure of human Leukotriene C4 synthase mutant R31Q in complex with glutathione== | |||
<StructureSection load='3leo' size='340' side='right'caption='[[3leo]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3leo]] 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=3LEO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LEO FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PAM:PALMITOLEIC+ACID'>PAM</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=3leo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3leo OCA], [https://pdbe.org/3leo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3leo RCSB], [https://www.ebi.ac.uk/pdbsum/3leo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3leo ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:[https://omim.org/entry/246530 246530]. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human leukotriene C(4) synthase (hLTC(4)S) is an integral membrane enzyme that conjugates leukotriene (LT) A(4) with glutathione to form LTC(4), a precursor to the cysteinyl leukotrienes (LTC(4), LTD(4), and LTE(4)) that are involved in the pathogenesis of human bronchial asthma. From the crystal structure of hLTC(4)S, Arg-104 and Arg-31 have been implicated in the conjugation reaction. Here, we used site-directed mutagenesis, UV spectroscopy, and x-ray crystallography to examine the catalytic role of Arg-104 and Arg-31. Exchange of Arg-104 with Ala, Ser, Thr, or Lys abolished 94.3-99.9% of the specific activity against LTA(4). Steady-state kinetics of R104A and R104S revealed that the K(m) for GSH was not significantly affected. UV difference spectra of the binary enzyme-GSH complex indicated that GSH ionization depends on the presence of Arg-104 because no thiolate signal, with lambda(max) at 239 nm, could be detected using R104A or R104S hLTC(4)S. Apparently, the interaction of Arg-104 with the thiol group of GSH reduces its pK(a) to allow formation of a thiolate anion and subsequent nucleophilic attack at C6 of LTA(4). On the other hand, exchange of Arg-31 with Ala or Glu reduced the catalytic activity of hLTC(4)S by 88 and 70%, respectively, without significantly affecting the k(cat)/K(m) values for GSH, and a crystal structure of R31Q hLTC(4)S (2.1 A) revealed a Gln-31 side chain pointing away from the active site. We conclude that Arg-104 plays a critical role in the catalytic mechanism of hLTC(4)S, whereas a functional role of Arg-31 seems more elusive. Because Arg-104 is a conserved residue, our results pertain to other homologous membrane proteins and represent a structure-function paradigm probably common to all microsomal GSH transferases. | |||
Arginine 104 is a key catalytic residue in leukotriene C4 synthase.,Rinaldo-Matthis A, Wetterholm A, Martinez Molina D, Holm J, Niegowski D, Ohlson E, Nordlund P, Morgenstern R, Haeggstrom JZ J Biol Chem. 2010 Dec 24;285(52):40771-6. Epub 2010 Oct 27. PMID:20980252<ref>PMID:20980252</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3leo" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Leukotriene C4 synthase|Leukotriene C4 synthase]] | *[[Leukotriene C4 synthase|Leukotriene C4 synthase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Haeggstrom | [[Category: Large Structures]] | ||
[[Category: Martinez-Molina | [[Category: Haeggstrom J]] | ||
[[Category: Niegowski | [[Category: Martinez-Molina D]] | ||
[[Category: Nordlund | [[Category: Niegowski D]] | ||
[[Category: Rinaldo-Matthis | [[Category: Nordlund P]] | ||
[[Category: Rinaldo-Matthis A]] | |||
