8T4O

Human mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and AGF347 inhibitor with no glutamate

8T4O の概要

• エントリーDOI: 10.2210/pdb8t4o/pdb
• 分子名称: Serine hydroxymethyltransferase, mitochondrial, 4-[4-(2-amino-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2-fluorobenzoic acid, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], ... (4 entities in total)
• 機能のキーワード: mitochondrial, one-carbon metabolism, polyglutamate, inhibitor, complex, serine and glycine metabolism, transferase
• 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: 110168.61

構造登録者

Katinas, J.M.,Dann III, C.E. (登録日: 2023-06-09, 公開日: 2024-02-21)

主引用文献

Katinas, J.M.,Nayeen, M.J.,Schneider, M.,Shah, K.,Fifer, A.N.,Klapper, L.M.,Sharma, A.,Thalluri, K.,Van Nieuwenhze, M.S.,Hou, Z.,Gangjee, A.,Matherly, L.H.,Dann 3rd, C.E.
Structural Characterization of 5-Substituted Pyrrolo[3,2- d ]pyrimidine Antifolate Inhibitors in Complex with Human Serine Hydroxymethyl Transferase 2.
Biochemistry, 2024

PubMed Abstract: We previously discovered first-in-class multitargeted 5-substituted pyrrolo[3,2-]pyrimidine antifolates that inhibit serine hydroxymethyltransferase 2 (SHMT2), resulting in potent in vitro and in vivo antitumor efficacies. In this report, we present crystallographic structures for SHMT2 in complex with an expanded series of pyrrolo[3,2-]pyrimidine compounds with variations in bridge length (3-5 carbons) and the side chain aromatic ring (phenyl, thiophene, fluorine-substituted phenyl, and thiophene). We evaluated structural features of the inhibitor-SHMT2 complexes and correlations to inhibitor potencies (i.e., s), highlighting conserved polar contacts and identifying 5-carbon bridge lengths as key determinants of inhibitor potency. Based on the analysis of SHMT2 structural data, we investigated the impact of mutation of Tyr105 in SHMT2 kinetic analysis and studies with HCT116 cells with inducible expression of wild-type and Y105F SHMT2. Increased enzyme inhibition potency by the pyrrolo[3,2-]pyrimidine inhibitors with Phe105 SHMT2 accompanied an increased growth inhibition of Phe105-expressing HCT116 cells compared to wild-type SHMT2. Pyrrolo[3,2-]pyrimidine inhibitors with polyglutamate modifications were evaluated for potencies against SHMT2. We determined the crystal structures of SHMT2 in complex with our lead antifolate AGF347 lacking L-glutamate, or as a diglutamate and triglutamate, for comparison with parent AGF347. These data provide the first insights into the influence of antifolate polyglutamylation on SHMT2:inhibitor interactions. Collectively, our results provide new insights into the critical structural determinants of SHMT2 binding by pyrrolo[3,2-]pyrimidine inhibitors as novel antitumor agents, as well as the first structural characterization of human SHMT2 in complex with polyglutamates of an SHMT2-targeted antifolate.

PubMed: 38324671
DOI: 10.1021/acs.biochem.3c00613

実験手法

X-RAY DIFFRACTION (2.68 Å)