Conformational flexibility within the small domain of human serine racemase
| Autor: | Chloe R. Koulouris, Benjamin D. Bax, John R. Atack, S. Mark Roe |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Protein Conformation Stereochemistry Racemases and Epimerases Biophysics Protein Data Bank (RCSB PDB) Isomerase Crystallography X-Ray Biochemistry Cofactor Research Communications Serine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains Structural Biology Catalytic Domain Genetics Humans Amino Acid Sequence Ion channel 030304 developmental biology 0303 health sciences biology Condensed Matter Physics Malonate chemistry Serine racemase biology.protein 030217 neurology & neurosurgery Ramachandran plot |
| Zdroj: | Acta Crystallogr F Struct Biol Commun |
| ISSN: | 2053-230X |
| Popis: | Serine racemase (SR) is a pyridoxal 5′-phosphate (PLP)-containing enzyme that converts L-serine to D-serine, an endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR) subtype of glutamate ion channels. SR regulates D-serine levels by the reversible racemization of L-serine to D-serine, as well as the catabolism of serine by α,β-elimination to produce pyruvate. The modulation of SR activity is therefore an attractive therapeutic approach to disorders associated with abnormal glutamatergic signalling since it allows an indirect modulation of NMDAR function. In the present study, a 1.89 Å resolution crystal structure of the human SR holoenzyme (including the PLP cofactor) with four subunits in the asymmetric unit is described. Comparison of this new structure with the crystal structure of human SR with malonate (PDB entry 3l6b) shows an interdomain cleft that is open in the holo structure but which disappears when the inhibitor malonate binds and is enclosed. This is owing to a shift of the small domain (residues 78–155) in human SR similar to that previously described for the rat enzyme. This domain movement is accompanied by changes within the twist of the central four-stranded β-sheet of the small domain, including changes in the φ–ψ angles of all three residues in the C-terminal β-strand (residues 149–151). In the malonate-bound structure, Ser84 (a catalytic residue) points its side chain at the malonate and is preceded by a six-residue β-strand (residues 78–83), but in the holoenzyme the β-strand is only four residues (78–81) and His82 has φ–ψ values in the α-helical region of the Ramachandran plot. These data therefore represent a crystallographic platform that enables the structure-guided design of small-molecule modulators for this important but to date undrugged target. |
| Databáze: | OpenAIRE |
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