8FJT

Human mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and AGF362 inhibitor

8FJT の概要

• エントリーDOI: 10.2210/pdb8fjt/pdb
• 分子名称: Serine hydroxymethyltransferase, mitochondrial, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], N-{4-[4-(2-amino-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-3-fluorothiophene-2-carbonyl}-L-glutamic acid, ... (6 entities in total)
• 機能のキーワード: shmt2, tetramer, glycine synthesis, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 110799.23

構造登録者

Katinas, J.M.,Dann III, C.E. (登録日: 2022-12-20, 公開日: 2023-09-06, 最終更新日: 2024-02-07)

主引用文献

Nayeen, M.J.,Katinas, J.M.,Magdum, T.,Shah, K.,Wong, J.E.,O'Connor, C.E.,Fifer, A.N.,Wallace-Povirk, A.,Hou, Z.,Matherly, L.H.,Dann 3rd, C.E.,Gangjee, A.
Structure-Based Design of Transport-Specific Multitargeted One-Carbon Metabolism Inhibitors in Cytosol and Mitochondria.
J.Med.Chem., 66:11294-11323, 2023

PubMed Abstract: Multitargeted agents provide tumor selectivity with reduced drug resistance and dose-limiting toxicities. We previously described the multitargeted 6-substituted pyrrolo[3,2-]pyrimidine antifolate with activity against early- and late-stage pancreatic tumors with limited tumor selectivity. Structure-based design with our human serine hydroxymethyl transferase (SHMT) 2 and glycinamide ribonucleotide formyltransferase (GARFTase) structures, and published X-ray crystal structures of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC), SHMT1, and folate receptor (FR) α and β afforded 11 analogues. Multitargeted inhibition and selective tumor transport were designed by providing promiscuous conformational flexibility in the molecules. Metabolite rescue identified mitochondrial C1 metabolism along with purine biosynthesis as the targeted pathways. We identified analogues with tumor-selective transport via FRs and increased SHMT2, SHMT1, and GARFTase inhibition (28-, 21-, and 11-fold, respectively) compared to . These multitargeted agents represent an exciting new structural motif for targeted cancer therapy with substantial advantages of selectivity and potency over clinically used antifolates.

PubMed: 37582241
DOI: 10.1021/acs.jmedchem.3c00763

実験手法

X-RAY DIFFRACTION (2.47 Å)