Crystal structure of the active form of native human thymidylate synthase in the absence of bound substrates
| Autor: | J. Bareille, Stéphane Réty, Patrick Deschamps, Nicolas Leulliot |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation alpha-Helical Stereochemistry Recombinant Fusion Proteins Genetic Vectors Biophysics Protein Data Bank (RCSB PDB) Gene Expression Crystallography X-Ray Biochemistry Thymidylate synthase Research Communications Substrate Specificity 03 medical and health sciences Residue (chemistry) chemistry.chemical_compound Structural Biology Catalytic Domain Genetics Escherichia coli Transferase Humans Protein Interaction Domains and Motifs Amino Acid Sequence Cloning Molecular 030102 biochemistry & molecular biology biology Drug discovery Chemistry DNA replication Active site Thymidylate Synthase Condensed Matter Physics 030104 developmental biology biology.protein Protein Conformation beta-Strand Protein Multimerization Thymidine Deoxyuracil Nucleotides Protein Binding |
| Popis: | Human thymidylate synthase (hTS) provides the solede novointracellular source of thymidine 5′-monophosphate (dTMP). hTS is required for DNA replication prior to cell division, making it an attractive target for anticancer chemotherapy and drug discovery. hTS binds 2′-deoxyuridine 5′-monophosphate (dUMP) and the folate co-substrateN5,N10-methylenetetrahydrofolate (meTHF) in a pocket near the catalytic residue Cys195. The catalytic loop, which is composed of amino-acid residues 181–197, can adopt two distinct conformations related by a 180° rotation. In the active conformation Cys195 is close to the active site, while in the inactive conformation it is rotated and Cys195 is too distant from the active site for catalysis. Several hTS structures, either native or engineered, have been solved in the active conformation in complex with ligands or inhibitors and at different salt concentrations. However, apo hTS structures have been solved in an inactive conformation in high-salt and low-salt conditions (PDB entries 1ypv, 4h1i, 4gyh, 3egy and 3ehi). Here, the structure of apo hTS crystallized in the active form with sulfate ions coordinated by the arginine residue that binds dUMP is reported. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|