8FJU

Human mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and AGF347 inhibitor

Summary for 8FJU

• Entry DOI: 10.2210/pdb8fju/pdb
• Descriptor: 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]-2-fluorobenzoyl}-L-glutamic acid, ... (4 entities in total)
• Functional Keywords: shmt2, tetramer, glycine synthesis, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 110771.18

Authors

Katinas, J.M.,Dann III, C.E. (deposition date: 2022-12-20, release date: 2023-09-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.51 Å)