6smr | pdb_00006smr

A. thaliana serine hydroxymethyltransferase isoform 4 (AtSHMT4) in complex with methotrexate

spinqualitylabelsall models 6smr, resolution 2.12Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6smr is a 4 chain structure with sequence from Arabidopsis thaliana. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.12Å Ligands: EDO, MTX, PLS, TRS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GLYC4_ARATH Catalyzes the interconversion of serine and glycine. Publication Abstract from PubMed Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo, 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria-human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics. Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models.,Ruszkowski M, Sekula B, Ruszkowska A, Contestabile R, Nogues I, Angelaccio S, Szczepaniak A, Dauter Z Sci Rep. 2019 Dec 23;9(1):19614. doi: 10.1038/s41598-019-56043-4. PMID:31873125 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine hydroxymethyltransferase 3D structures

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