9box
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 9box is ON HOLD until Paper Publication Authors: Drago, V.N., Kovalevsky, A. Description: Room-temperature X-ray structure of human mitochondrial s...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Room-temperature X-ray structure of human mitochondrial serine hydroxymethyltransferase (hSHMT2) with PLP-glycine external aldimine and 5-formyltetrahydrofolate (folinic acid)== | |
| + | <StructureSection load='9box' size='340' side='right'caption='[[9box]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9box]] 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=9BOX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9BOX 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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9box FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9box OCA], [https://pdbe.org/9box PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9box RCSB], [https://www.ebi.ac.uk/pdbsum/9box PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9box ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [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 == | ||
| + | Serine hydroxymethyltransferase (SHMT) is a key enzyme in the one-carbon metabolic pathway, utilizing the vitamin B(6) derivative pyridoxal 5'-phosphate (PLP) and vitamin B(9) derivative tetrahydrofolate (THF) coenzymes to produce essential biomolecules. Many types of cancer utilize SHMT in metabolic reprogramming, exposing the enzyme as a compelling target for antimetabolite chemotherapies. In pursuit of elucidating the catalytic mechanism of SHMT to aid in the design of SHMT-specific inhibitors, we have used room-temperature neutron crystallography to directly determine the protonation states in a model enzyme Thermus thermophilus SHMT (TthSHMT), which exhibits a conserved active site compared to human mitochondrial SHMT2 (hSHMT2). Here we report the analysis of TthSHMT, with PLP in the internal aldimine form and bound THF-analog, folinic acid (FA), by neutron crystallography to reveal H atom positions in the active site, including PLP and FA. We observed protonated catalytic Glu53 revealing its ability to change protonation state upon FA binding. Furthermore, we obtained X-ray structures of TthSHMT-Gly/FA, TthSHMT-l-Ser/FA, and hSHMT2-Gly/FA ternary complexes with the PLP-Gly or PLP-l-Ser external aldimines to analyze the active site configuration upon PLP reaction with an amino acid substrate and FA binding. Accurate mapping of the active site protonation states together with the structural information gained from the ternary complexes allow us to suggest an essential role of the gating loop conformational changes in the SHMT function and to propose Glu53 as the universal acid-base catalyst in both THF-independent and THF-dependent activities of SHMT. | ||
| - | + | Universality of critical active site glutamate as an acid-base catalyst in serine hydroxymethyltransferase function.,Drago VN, Phillips RS, Kovalevsky A Chem Sci. 2024 Jul 3;15(32):12827-12844. doi: 10.1039/d4sc03187c. eCollection , 2024 Aug 14. PMID:39148791<ref>PMID:39148791</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Drago | + | <div class="pdbe-citations 9box" style="background-color:#fffaf0;"></div> |
| - | [[Category: Kovalevsky | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Drago VN]] | ||
| + | [[Category: Kovalevsky A]] | ||
Current revision
Room-temperature X-ray structure of human mitochondrial serine hydroxymethyltransferase (hSHMT2) with PLP-glycine external aldimine and 5-formyltetrahydrofolate (folinic acid)
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