Slipknot or Crystallographic Error: A Computational Analysis of the Plasmodium falciparum DHFR Structural Folds
| Autor: | Tata, Rolland B, Alsulami, Ali F, Sheik Amamuddy, Olivier, Blundell, Tom, Tastan Bishop, ��zlem |
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| Přispěvatelé: | Tata, Rolland B [0000-0002-8814-5241], Sheik Amamuddy, Olivier [0000-0002-1781-1382], Tastan Bishop, Özlem [0000-0001-6861-7849], Apollo - University of Cambridge Repository, Blundell, Tom [0000-0002-2708-8992] |
| Rok vydání: | 2022 |
| Předmět: |
Models
Molecular PDB Protein Folding QH301-705.5 Protein Conformation Plasmodium falciparum P. falciparum DHFR atypical folds slipknots crystallographic error Protozoan Proteins Molecular Dynamics Simulation Crystallography X-Ray Catalysis Inorganic Chemistry Protein Domains Sequence Analysis Protein parasitic diseases Physical and Theoretical Chemistry Biology (General) Databases Protein Molecular Biology QD1-999 Spectroscopy Sequence Homology Amino Acid Organic Chemistry General Medicine Computer Science Applications Chemistry Tetrahydrofolate Dehydrogenase Sequence Alignment |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 3; Pages: 1514 International Journal of Molecular Sciences, Vol 23, Iss 1514, p 1514 (2022) |
| DOI: | 10.17863/cam.82621 |
| Popis: | The presence of protein structures with atypical folds in the Protein Data Bank (PDB) is rare and may result from naturally occurring knots or crystallographic errors. Proper characterisation of such folds is imperative to understanding the basis of naturally existing knots and correcting crystallographic errors. If left uncorrected, such errors can frustrate downstream experiments that depend on the structures containing them. An atypical fold has been identified in P. falciparum dihydrofolate reductase (PfDHFR) between residues 20–51 (loop 1) and residues 191–205 (loop 2). This enzyme is key to drug discovery efforts in the parasite, necessitating a thorough characterisation of these folds. Using multiple sequence alignments (MSA), a unique insert was identified in loop 1 that exacerbates the appearance of the atypical fold-giving it a slipknot-like topology. However, PfDHFR has not been deposited in the knotted proteins database, and processing its structure failed to identify any knots within its folds. The application of protein homology modelling and molecular dynamics simulations on the DHFR domain of P. falciparum and those of two other organisms (E. coli and M. tuberculosis) that were used as molecular replacement templates in solving the PfDHFR structure revealed plausible unentangled or open conformations of these loops. These results will serve as guides for crystallographic experiments to provide further insights into the atypical folds identified. |
| Databáze: | OpenAIRE |
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