4JEF

Crystal structure of human thymidylate synthase Y202A in inactive conformation.

4JEF の概要

• エントリーDOI: 10.2210/pdb4jef/pdb
• 関連するPDBエントリー: 3EGY 3EHI 4E28 4FGT
• 分子名称: Thymidylate synthase, SULFATE ION (3 entities in total)
• 機能のキーワード: inactive form of human thymidylate synthase, hot spot residue, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P04818
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33213.97

構造登録者

Tochowicz, A.,Stroud, R.M.,Wade, R.C. (登録日: 2013-02-26, 公開日: 2014-08-20, 最終更新日: 2024-10-16)

主引用文献

Salo-Ahen, O.M.,Tochowicz, A.,Pozzi, C.,Cardinale, D.,Ferrari, S.,Boum, Y.,Mangani, S.,Stroud, R.M.,Saxena, P.,Myllykallio, H.,Costi, M.P.,Ponterini, G.,Wade, R.C.
Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase.
J.Med.Chem., 58:3572-3581, 2015

PubMed Abstract: Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the intersubunit interaction. Dimer dissociation constants measured by a FRET-based assay range from 60 nM for wild-type hTS up to about 1 mM for single-point mutants and agree with computational predictions of the effects of these mutations. Mutations that are remote from the active site retain full or partial activity, although the substrate KM values were generally higher and the dimer was less stable. The lower dimer stability of the mutants can facilitate access to the dimer interface by small molecules and thereby aid the design of inhibitors that bind at the dimer interface.

PubMed: 25798950
DOI: 10.1021/acs.jmedchem.5b00137

実験手法

X-RAY DIFFRACTION (2.311 Å)