9o50

Room-temperature X-ray structure of Thermus thermophilus SHMT in complex with tetrahydrofolate (THF)

spinqualitylabelsall models 9o50, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9o50 is a 2 chain structure with sequence from Thermus thermophilus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: LLP, SO4, THG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Serine hydroxymethyltransferase (SHMT) is a critical enzyme in the one-carbon (1C) metabolism pathway catalyzing the reversible conversion of L-Ser into Gly and concurrent transfer of 1C unit to tetrahydrofolate (THF) to give 5,10-methylene-THF (5,10-MTHF), which is used in the downstream syntheses of biomolecules critical for cell proliferation. The cellular 1C metabolism is hijacked by many cancer types to support cancer cell proliferation, making SHMT a promising target for the design and development of novel small-molecule antimetabolite chemotherapies. To advance structure-assisted drug design, knowledge of SHMT catalysis is crucial, but can only be fully realized when the atomic details of each reaction step governed by the acid-base catalysis are elucidated by visualizing active site hydrogen atoms. Here, we used room-temperature neutron crystallography to directly determine protonation states in Thermus thermophilus SHMT (TthSHMT), capturing protomer A in the apo form lacking the coenzyme pyridoxal 5'-phosphate (PLP), and protomer B as a ternary complex with PLP-Gly-external aldimine and (6S)-5-methyltetrahydrofolate (5MTHF). We observed protonation of the Schiff base nitrogen in PLP-Gly and neutrality of the catalytic Lys226 side chain in the ternary complex, whereas Lys226 is protonated and positively charged in the apo-active site. Furthermore, we obtained an X-ray structure of TthSHMT in complex with the substrate THF, which binds identically as 5MTHF at the peripheral binding site. The unique structural and functional information provided by neutron crystallography, in combination with X-ray structures, can be employed in the rational design of SHMT inhibitors. Neutron diffraction reveals protonation states in pyridoxal-5'-phosphate-free and glycine external aldimine-bound serine hydroxymethyltransferase.,Drago VN, Blakeley MP, Phillips RS, Kovalevsky A FEBS J. 2026 Jan;293(2):582-597. doi: 10.1111/febs.70260. Epub 2025 Sep 7. PMID:40915980 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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