5x2l: Difference between revisions

Revision as of 07:22, 7 October 2020

Crystal Structure of Human Serine Racemase

Structural highlights

5x2l is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	MG, PLP
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR. Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR.

Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase.,Takahara S, Nakagawa K, Uchiyama T, Yoshida T, Matsumoto K, Kawasumi Y, Mizuguchi M, Obita T, Watanabe Y, Hayakawa D, Gouda H, Mori H, Toyooka N Bioorg Med Chem Lett. 2017 Dec 13. pii: S0960-894X(17)31180-0. doi:, 10.1016/j.bmcl.2017.12.021. PMID:29277459^[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
↑ Takahara S, Nakagawa K, Uchiyama T, Yoshida T, Matsumoto K, Kawasumi Y, Mizuguchi M, Obita T, Watanabe Y, Hayakawa D, Gouda H, Mori H, Toyooka N. Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase. Bioorg Med Chem Lett. 2017 Dec 13. pii: S0960-894X(17)31180-0. doi:, 10.1016/j.bmcl.2017.12.021. PMID:29277459 doi:https://dx.doi.org/10.1016/j.bmcl.2017.12.021

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OCA

[1] 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

[2] 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

[3] Takahara S, Nakagawa K, Uchiyama T, Yoshida T, Matsumoto K, Kawasumi Y, Mizuguchi M, Obita T, Watanabe Y, Hayakawa D, Gouda H, Mori H, Toyooka N. Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase. Bioorg Med Chem Lett. 2017 Dec 13. pii: S0960-894X(17)31180-0. doi:, 10.1016/j.bmcl.2017.12.021. PMID:29277459 doi:https://dx.doi.org/10.1016/j.bmcl.2017.12.021

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Human Serine Racemase==
-<StructureSection load='5x2l' size='340' side='right' caption='[[5x2l]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
+<StructureSection load='5x2l' size='340' side='right'caption='[[5x2l]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5x2l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X2L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5X2L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5x2l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X2L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5X2L 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=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></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=5x2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x2l OCA], [http://pdbe.org/5x2l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x2l RCSB], [http://www.ebi.ac.uk/pdbsum/5x2l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x2l ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5x2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x2l OCA], [http://pdbe.org/5x2l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x2l RCSB], [http://www.ebi.ac.uk/pdbsum/5x2l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x2l ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Matsumoto, K]]
 [[Category: Mizuguchi, M]]

5x2l: Difference between revisions

Revision as of 07:22, 7 October 2020

Crystal Structure of Human Serine Racemase

Structural highlights

Function

Publication Abstract from PubMed

References

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