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5v7i

From Proteopedia

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Crystal structure of homo sapiens serine hydroxymethyltransferase 2 (mitochondrial) (SHMT2), in complex with glycine, PLP and folate-competitive pyrazolopyran inhibitor: 6-amino-4-isopropyl-3-methyl-4-(3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

Structural highlights

5v7i is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.47Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GLYM_HUMAN Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Interconversion of serine and glycine. Associates with mitochondrial DNA.^[1]

Publication Abstract from PubMed

The enzyme serine hydroxymethyltransferse (SHMT) converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Folate one-carbon units support purine and thymidine synthesis, and thus cell growth. Mammals have both cytosolic SHMT1 and mitochondrial SHMT2, with the mitochondrial isozyme strongly up-regulated in cancer. Here we show genetically that dual SHMT1/2 knockout blocks HCT-116 colon cancer tumor xenograft formation. Building from a pyrazolopyran scaffold that inhibits plant SHMT, we identify small-molecule dual inhibitors of human SHMT1/2 (biochemical IC50 approximately 10 nM). Metabolomics and isotope tracer studies demonstrate effective cellular target engagement. A cancer cell-line screen revealed that B-cell lines are particularly sensitive to SHMT inhibition. The one-carbon donor formate generally rescues cells from SHMT inhibition, but paradoxically increases the inhibitor's cytotoxicity in diffuse large B-cell lymphoma (DLBCL). We show that this effect is rooted in defective glycine uptake in DLBCL cell lines, rendering them uniquely dependent upon SHMT enzymatic activity to meet glycine demand. Thus, defective glycine import is a targetable metabolic deficiency of DLBCL.

Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma.,Ducker GS, Ghergurovich JM, Mainolfi N, Suri V, Jeong SK, Hsin-Jung Li S, Friedman A, Manfredi MG, Gitai Z, Kim H, Rabinowitz JD Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11404-11409. doi:, 10.1073/pnas.1706617114. Epub 2017 Oct 9. PMID:29073064^[2]

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

References

↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
↑ Ducker GS, Ghergurovich JM, Mainolfi N, Suri V, Jeong SK, Hsin-Jung Li S, Friedman A, Manfredi MG, Gitai Z, Kim H, Rabinowitz JD. Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11404-11409. doi:, 10.1073/pnas.1706617114. Epub 2017 Oct 9. PMID:29073064 doi:http://dx.doi.org/10.1073/pnas.1706617114

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5v7i"

@@ Line 3: / Line 3: @@
 <StructureSection load='5v7i' size='340' side='right'caption='[[5v7i]], [[Resolution|resolution]] 2.47&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5v7i]] is a 2 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=5V7I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V7I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5v7i]] 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=5V7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V7I FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8Z1:(4R)-6-amino-3-methyl-4-(propan-2-yl)-4-[3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl]-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile'>8Z1</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.47&#8491;</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=8Z1:(4R)-6-amino-3-methyl-4-(propan-2-yl)-4-[3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl]-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile'>8Z1</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <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=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SHMT2 ([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=5v7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v7i OCA], [https://pdbe.org/5v7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v7i RCSB], [https://www.ebi.ac.uk/pdbsum/5v7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v7i ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glycine_hydroxymethyltransferase Glycine hydroxymethyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.2.1 2.1.2.1] </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=5v7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v7i OCA], [http://pdbe.org/5v7i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v7i RCSB], [http://www.ebi.ac.uk/pdbsum/5v7i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v7i ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GLYM_HUMAN GLYM_HUMAN]] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Interconversion of serine and glycine. Associates with mitochondrial DNA.<ref>PMID:21876188</ref>
+[https://www.uniprot.org/uniprot/GLYM_HUMAN GLYM_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Interconversion of serine and glycine. Associates with mitochondrial DNA.<ref>PMID:21876188</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 21: @@
 ==See Also==
-*[[Serine hydroxymethyltransferase|Serine hydroxymethyltransferase]]
+*[[Serine hydroxymethyltransferase 3D structures|Serine hydroxymethyltransferase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Glycine hydroxymethyltransferase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Ducker, G S]]
+[[Category: Ducker GS]]
-[[Category: Friedman, A]]
+[[Category: Friedman A]]
-[[Category: Ghergurovich, J M]]
+[[Category: Ghergurovich JM]]
-[[Category: Jeong, S]]
+[[Category: Jeong S]]
-[[Category: Kim, H]]
+[[Category: Kim H]]
-[[Category: Mainolfi, N]]
+[[Category: Mainolfi N]]
-[[Category: Manfredi, M]]
+[[Category: Manfredi M]]
-[[Category: Rabinowitz, J D]]
+[[Category: Rabinowitz JD]]
-[[Category: Suri, V]]
+[[Category: Suri V]]
-[[Category: Antifolate]]
-[[Category: Serine catabolism]]
-[[Category: Shmt2]]
-[[Category: Transferase-transferase inhibitor complex]]

5v7i

From Proteopedia

Current revision

Crystal structure of homo sapiens serine hydroxymethyltransferase 2 (mitochondrial) (SHMT2), in complex with glycine, PLP and folate-competitive pyrazolopyran inhibitor: 6-amino-4-isopropyl-3-methyl-4-(3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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