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| | <StructureSection load='6slh' size='340' side='right'caption='[[6slh]], [[Resolution|resolution]] 1.89Å' scene=''> | | <StructureSection load='6slh' size='340' side='right'caption='[[6slh]], [[Resolution|resolution]] 1.89Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6slh]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SLH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6SLH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6slh]] is a 4 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=6SLH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SLH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></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]] 1.89Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SRR ([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'>[https://proteopedia.org/fgij/fg.htm?mol=6slh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6slh OCA], [https://pdbe.org/6slh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6slh RCSB], [https://www.ebi.ac.uk/pdbsum/6slh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6slh 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=6slh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6slh OCA], [http://pdbe.org/6slh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6slh RCSB], [http://www.ebi.ac.uk/pdbsum/6slh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6slh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SRR_HUMAN SRR_HUMAN]] Catalyzes the synthesis of D-serine from L-serine. D-serine is a key coagonist with glutamate at NMDA receptors. Has dehydratase activity towards both L-serine and D-serine.<ref>PMID:11054547</ref> <ref>PMID:20106978</ref> | + | [https://www.uniprot.org/uniprot/SRR_HUMAN SRR_HUMAN] Catalyzes the synthesis of D-serine from L-serine. D-serine is a key coagonist with glutamate at NMDA receptors. Has dehydratase activity towards both L-serine and D-serine.<ref>PMID:11054547</ref> <ref>PMID:20106978</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Atack, J]] | + | [[Category: Atack J]] |
| - | [[Category: Bax, B]] | + | [[Category: Bax B]] |
| - | [[Category: Koulouris, C R]] | + | [[Category: Koulouris CR]] |
| - | [[Category: Roe, S M]] | + | [[Category: Roe SM]] |
| - | [[Category: D-serine]]
| + | |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Nmda receptor]]
| + | |
| - | [[Category: Plp-dependent]]
| + | |
| - | [[Category: Racemization]]
| + | |
| Structural highlights
Function
SRR_HUMAN Catalyzes the synthesis of D-serine from L-serine. D-serine is a key coagonist with glutamate at NMDA receptors. Has dehydratase activity towards both L-serine and D-serine.[1] [2]
Publication Abstract from PubMed
Serine racemase (SR) is a pyridoxal 5'-phosphate (PLP)-containing enzyme that converts L-serine to D-serine, an endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR) subtype of glutamate ion channels. SR regulates D-serine levels by the reversible racemization of L-serine to D-serine, as well as the catabolism of serine by alpha,beta-elimination to produce pyruvate. The modulation of SR activity is therefore an attractive therapeutic approach to disorders associated with abnormal glutamatergic signalling since it allows an indirect modulation of NMDAR function. In the present study, a 1.89 A resolution crystal structure of the human SR holoenzyme (including the PLP cofactor) with four subunits in the asymmetric unit is described. Comparison of this new structure with the crystal structure of human SR with malonate (PDB entry 3l6b) shows an interdomain cleft that is open in the holo structure but which disappears when the inhibitor malonate binds and is enclosed. This is owing to a shift of the small domain (residues 78-155) in human SR similar to that previously described for the rat enzyme. This domain movement is accompanied by changes within the twist of the central four-stranded beta-sheet of the small domain, including changes in the phi-psi angles of all three residues in the C-terminal beta-strand (residues 149-151). In the malonate-bound structure, Ser84 (a catalytic residue) points its side chain at the malonate and is preceded by a six-residue beta-strand (residues 78-83), but in the holoenzyme the beta-strand is only four residues (78-81) and His82 has phi-psi values in the alpha-helical region of the Ramachandran plot. These data therefore represent a crystallographic platform that enables the structure-guided design of small-molecule modulators for this important but to date undrugged target.
Conformational flexibility within the small domain of human serine racemase.,Koulouris CR, Bax BD, Atack JR, Roe SM Acta Crystallogr F Struct Biol Commun. 2020 Feb 1;76(Pt 2):65-73. doi:, 10.1107/S2053230X20001193. Epub 2020 Feb 3. PMID:32039887[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ De Miranda J, Santoro A, Engelender S, Wolosker H. Human serine racemase: moleular cloning, genomic organization and functional analysis. Gene. 2000 Oct 3;256(1-2):183-8. PMID:11054547
- ↑ Smith MA, Mack V, Ebneth A, Moraes I, Felicetti B, Wood M, Schonfeld D, Mather O, Cesura A, Barker J. The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding. J Biol Chem. 2010 Apr 23;285(17):12873-81. Epub 2010 Jan 27. PMID:20106978 doi:10.1074/jbc.M109.050062
- ↑ Koulouris CR, Bax BD, Atack JR, Roe SM. Conformational flexibility within the small domain of human serine racemase. Acta Crystallogr F Struct Biol Commun. 2020 Feb 1;76(Pt 2):65-73. doi:, 10.1107/S2053230X20001193. Epub 2020 Feb 3. PMID:32039887 doi:http://dx.doi.org/10.1107/S2053230X20001193
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