2nmp

From Proteopedia

(Difference between revisions)

Revision as of 17:20, 15 August 2018

Crystal structure of human Cystathionine gamma lyase

Structural highlights

2nmp is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	CTH (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CGL_HUMAN] Defects in CTH are the cause of cystathioninuria (CSTNU) [MIM:219500]. It is an autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion.^[1] ^[2]

Function

[CGL_HUMAN] Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function.^[3] ^[4] ^[5]

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

Impairment of the formation or action of hydrogen sulfide (H(2)S), an endogenous gasotransmitter, is associated with various diseases, such as hypertension, diabetes mellitus, septic and hemorrhagic shock, and pancreatitis. Cystathionine beta-synthase and cystathionine gamma-lyase (CSE) are two pyridoxal-5'-phosphate (PLP)-dependent enzymes largely responsible for the production of H(2)S in mammals. Inhibition of CSE by DL-propargylglycine (PAG) has been shown to alleviate disease symptoms. Here we report crystal structures of human CSE (hCSE), in apo form, and in complex with PLP and PLP.PAG. Structural characterization, combined with biophysical and biochemical studies, provides new insights into the inhibition mechanism of hCSE-mediated production of H(2)S. Transition from the open form of apo-hCSE to the closed PLP-bound form reveals large conformational changes hitherto not reported. In addition, PAG binds hCSE via a unique binding mode, not observed in PAG-enzyme complexes previously. The interaction of PAG-hCSE was not predicted based on existing information from known PAG complexes. The structure of hCSE.PLP.PAG complex highlights the particular importance of Tyr(114) in hCSE and the mechanism of PAG-dependent inhibition of hCSE. These results provide significant insights, which will facilitate the structure-based design of novel inhibitors of hCSE to aid in the development of therapies for diseases involving disorders of sulfur metabolism.

Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S.,Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J J Biol Chem. 2009 Jan 30;284(5):3076-85. Epub 2008 Nov 19. PMID:19019829^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhu W, Lin A, Banerjee R. Kinetic properties of polymorphic variants and pathogenic mutants in human cystathionine gamma-lyase. Biochemistry. 2008 Jun 10;47(23):6226-32. doi: 10.1021/bi800351a. Epub 2008 May, 14. PMID:18476726 doi:10.1021/bi800351a
↑ Wang J, Hegele RA. Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH). Hum Genet. 2003 Apr;112(4):404-8. Epub 2003 Feb 6. PMID:12574942 doi:10.1007/s00439-003-0906-8
↑ Chiku T, Padovani D, Zhu W, Singh S, Vitvitsky V, Banerjee R. H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem. 2009 Apr 24;284(17):11601-12. doi: 10.1074/jbc.M808026200. Epub 2009, Mar 4. PMID:19261609 doi:10.1074/jbc.M808026200
↑ Krishnan N, Fu C, Pappin DJ, Tonks NK. H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci Signal. 2011 Dec 13;4(203):ra86. doi: 10.1126/scisignal.2002329. PMID:22169477 doi:10.1126/scisignal.2002329
↑ Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J. Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S. J Biol Chem. 2009 Jan 30;284(5):3076-85. Epub 2008 Nov 19. PMID:19019829 doi:http://dx.doi.org/10.1074/jbc.M805459200
↑ Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J. Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S. J Biol Chem. 2009 Jan 30;284(5):3076-85. Epub 2008 Nov 19. PMID:19019829 doi:http://dx.doi.org/10.1074/jbc.M805459200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2nmp"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human Cystathionine gamma lyase==
 <StructureSection load='2nmp' size='340' side='right' caption='[[2nmp]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2nmp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nmp OCA], [http://pdbe.org/2nmp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2nmp RCSB], [http://www.ebi.ac.uk/pdbsum/2nmp PDBsum]</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=2nmp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nmp OCA], [http://pdbe.org/2nmp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2nmp RCSB], [http://www.ebi.ac.uk/pdbsum/2nmp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2nmp ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 15: / Line 16: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nm/2nmp_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nm/2nmp_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>

2nmp

From Proteopedia

Revision as of 17:20, 15 August 2018

Crystal structure of human Cystathionine gamma lyase

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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