China
Africa
Explore chapters and articles related to this topic
Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
When a drug is required to supress the activity of a receptor, binding interactions must be designed so that the drug behaves as an antagonist. Molecular modelling and x-ray crystallography can be used to reveal the structure of the binding site, which enables deduction of drug pharmacodynamics so that binding groups can be positioned on the target molecule to produce a drug that binds to the receptor, but in such a way that the change in conformation of the protein receptor is incorrect for propagating a response to the signal. Generating a library of target molecules, each with slightly different binding properties to find a potentially successful drug; the suite of molecules can be screened against the binding site to optimise the pharmacokinetics and yield a final medicinally useful compound.
Therapeutic Strategies and Future Research
Published in Mark A. Mentzer, Mild Traumatic Brain Injury, 2020
X-ray crystallography provides another means to characterize the atomic structure of crystalline materials. (Rosalind Franklin used the technique to produce the famous demonstration that DNA is helical.) This characterization includes proteins and nucleic acids. While certain proteins are difficult to crystallize, nearly 50,000 proteins, nucleic acids and other biological macromolecules have now been measured with X-ray crystallography (Scapin, 2006; Lundstrom, 2006).
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The determination of the exact structure of the ligand-binding pocket within the DARs has long been a challenging endeavor. Scientists typically resolve the chemical structure of a protein by means of X-ray crystallography. For that, various methods are used to induce the protein to condense into a tightly packed crystal lattice. Once this is achieved, X-rays are delivered to the crystal and the structure of the protein is resolved from the diffraction patterns. However, getting the DAR proteins to crystalize with a bound ligand had been problematic for many years. This difficulty stems from the fact that membrane-embedded receptors are notoriously difficult proteins for crystallization because of their low abundance and hydrophobicity. In fact, of the five DAR subtypes, only the D3R has been successfully crystallized.
Electron microscopy overview of SARS-COV2 and its clinical impact
Published in Ultrastructural Pathology, 2022
Soheir Saiid Mansy, Mona Mahmoud AbouSamra
Many techniques, including NMR spectroscopy, X-ray solution scattering, neutron diffraction, various spectroscopic techniques, and X-ray crystallography, have been used to determine the shape and structure of biological molecules. Recently, cryo-electron microscopy has become the most effective tool in structural biology after the technical development of its resolutions, which permits the identification of the biomolecular structure in its natural state.59 Cryo-EM has an advantage over X-ray crystallography, and is the most effective tool in analyzing macromolecules during the last few years. Cryo-EM reveals structures in fast-frozen non-crystalline biological samples that are closer to their natural state at an atomic level. In addition, it requires much smaller macromolecule samples to work with, unlike X-ray crystallography, which needs large pieces of materials to optimize the crystallization conditions.59 Hence, cryo-EM has become the tool of choice for determining the structure of macromolecular complexes, especially supra-assemblies that are difficult to prepare in large quantities or virtually inaccessible to crystallize.59,61,62 Identifying the structural biology of viral protein complexes at molecular resolution is important for designing small drug molecules to bind and impair their function.32
Targeting thermoTRP ion channels: in silico preclinical approaches and opportunities
Published in Expert Opinion on Therapeutic Targets, 2020
Gregorio Fernández-Ballester, Asia Fernández-Carvajal, Antonio Ferrer-Montiel
X-ray crystallography has been the traditional tool used by structural biologists to solve protein structures. To date, about 160,000 protein structures have been published in the Protein Data Bank (PDB), with near 10,000 new structures added every year. For X-ray crystallography, the target protein has to be expressed, purified near to homogeneity to obtain protein crystals with good diffraction patterns. Diffracting crystals are essential for building an accurate structural model where the three-dimensional spatial position of each atom can be mapped. An important limiting step in protein crystallization is to empirically establish the conditions for getting diffracting protein crystals. Presently, concentrated protein solutions are subjected in parallel to a wide variety of crystallization conditions using the drop diffusion technique. This technique allows the screening of a variety of crystallization conditions close to an HTS format.
Characterization of the phosphotransacetylase-acetate kinase pathway for ATP production in Porphyromonas gingivalis
Published in Journal of Oral Microbiology, 2019
Yasuo Yoshida, Mitsunari Sato, Takamasa Nonaka, Yoshiaki Hasegawa, Yuichiro Kezuka
Since P. gingivalis produces a large amount of short chain fatty acids, including acetate, propionate, and butyrate [23], it is postulated that the Pta-Ack pathway, which is associated with acetate production, is conserved in P. gingivalis [8,9] (Figure 1). Despite the importance of Pta and Ack in carbon cycling and energy metabolism in P. gingivalis, these enzymes have not been characterized in this microorganism, even though the coding genes have been assigned based on sequence homology [24,25]. In the current study, recombinant Pta (PgPta) and Ack (PgAck) from P. gingivalis ATCC 33277, encoded by pta (PGN_1179) and ack (PGN_1178), respectively, were prepared and enzymatically characterized. In addition, crystal structures were determined by X-ray crystallography. Based on the structures, several putative functional residues were identified and their contribution to catalytic activity was evaluated by site-directed mutagenesis. Furthermore, we examined the essentiality of pta and ack in P. gingivalis.