Superoxide Dismutase, Mitochondrial Dysfunction, and Neurodegenerative Diseases
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
ALS prognosis correlates with the extent of IC-CuZnSOD aggregation into fibrils, much like amyloid-β fibrils in Alzheimer’s disease [70]. Fibrils form by IC-CuZnSOD misfolding and self-association into high-order, low energy structures. Examples are metal-deficient variants that destabilize the tertiary structure of the protein, and non-native interactions are energetically favored [116]. Other variants, affecting monomer structure and stability of the dimer interface, are thought to aggregate into fibrils as a result of lower thermostability and increased disorder [70,116]. Protein fold stability is further compromised through a lack of disulfide bond formation. Despite the cytosol being a strong reducing environment, IC-CuZnSOD harbors an oxidized disulfide bond that is buried near the dimer interface in WT. Variants that decrease dimer stability and expose the bond are more susceptible to disulfide reduction by glutathione/glutaredoxin systems [134]. A lack of Cu or Zn metallation also decreases dimer stability, meaning variants that compromise metal binding also expose the disulfide bond for reduction. The propensity for IC-CuZnSOD to form fibrils is related to factors compromising its stability, such as mutations and reduced disulfide bonds.
Conclusions
Kiheung Kim in The Social Construction of Disease, 2006
Recently, there have been many interesting developments in this field; the storm cloud of controversy seems to be lifting, thanks to scientific breakthroughs. The main issue remaining before the puzzle of prion theory can finally be solved is widely acknowledged to be the problem of showing what makes protein fold incorrectly in artificial settings (i.e. when making infectious protein in the laboratory test tube). As mentioned in the previous chapters, many scientists attempted to reproduce the prion protein artificially, and to make the artificial protein infectious in order to cause the brain disease in healthy laboratory animals. However, all attempts at making a synthetic form of infectious protein were unsuccessful. Because of this constant failure, some scientists are still reluctant to commit to the prion theory, and continue to cast doubt on whether the prion protein is the main suspect (Chesebro 1998; Caughey and Kocisko 2003; Manuelidis 2003). Although some researchers had actually already reported they had made the synthetic form of abnormal prion protein successfully during the 1990s (Kocisko et al. 1994), they still could not show or prove that the synthetic prion protein was indeed the infectious agent.
Microbial Pathways of Lipid A Biosynthesis
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
Lipid A synthesis is initiated by the transfer of the (R)-3-hydroxymyristate moiety from (R)-3-hydroxymyristoyl-acyl-carrier-protein (ACP) to the 3′-hydroxyl of UDP-GlcNAc to yield UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetyl-D-glucosamine (UDP-3-O-monoacyl-N-acetylglucosamine) (48). This reaction is catalyzed by the cytosolic enzyme UDP-N-acetylglucosamine acyltransferase (LpxA) (48,49). The IpxA gene has been cloned and sequenced, and it is located clockwise of dnaE at min 4 on the E. coli chromosome as part of a complex operon that includes three other genes involved in lipid A synthesis (lpxB,fabZ, and firA[lpxD]) as well as several additional open reading frames of unknown function (49–52). The deduced amino acid sequence of LpxA revealed it to be a 28 kDa protein comprised of 262 amino acids (50), and the enzyme has been purified to near homogeneity (53). Indeed, the x-ray crystal structure of the enzyme has been determined to 2.6 Å resolution, and an atomic model of LpxA based on the crystallographic data revealed the enzyme to be comprised of three identical subunits and a new kind of helical protein fold (54). The active site appears to be situated between the subunits. LpxA is the only acyltransferase for which a crystal structure is available.
Artificial intelligence in early drug discovery enabling precision medicine
Published in Expert Opinion on Drug Discovery, 2021
Fabio Boniolo, Emilio Dorigatti, Alexander J. Ohnmacht, Dieter Saur, Benjamin Schubert, Michael P. Menden
The use of co-evolutionary sequence information has also led to new breakthroughs in protein structure prediction, as demonstrated in the two latest CASP competitions by AlphaFold [173]. This model uses predicted structural contacts from co-evolutionary models and refines them with a deep residual network that predicts the distribution of contact distances. These are interpreted as the statistical energy of the protein fold and directly minimized to yield highly accurate 3D protein structures. Since then, extensions have been made to remove the dependency on co-evolutionary analysis further [174], making it possible to predict 3D structures of artificial proteins and protein families starting from only a few sequences. Others have started to develop neural protein folding simulators that are fully trainable in an end-to-end-fashion and can directly map sequence to structure [175,176].
CALR-ETdb, the database of calreticulin variants diversity in essential thrombocythemia
Published in Platelets, 2022
Nora El Jahrani, Gabriel Cretin, Alexandre G. de Brevern
To improve the models, we added constraints on the positioning of the helices. The positions used were the positions with high confidence index. Type 1 DOPE scores decreased strongly, demonstrating better “globularity” in terms of the protein structure-sequence relationship. However, the best DOPE score had an unexpected additional helix, so another model for type 1 with a very close DOPE score was selected. For the type 2 models, the best DOPE score was still associated with a misplaced helix, so another model with a close DOPE score was chosen, but the model was therefore structurally further away. The two models selected consequently exhibited protein folds with helices corresponding to the expected data (see Figure 4a and b).
Promiscuity in drug discovery on the verge of the structural revolution: recent advances and future chances
Published in Expert Opinion on Drug Discovery, 2023
Sarah Naomi Bolz, Michael Schroeder
The fundamental reason why drug repositioning is a viable effort to drug discovery is the promiscuity of drugs and targets. Often a drug can bind many targets and a target can be bound by many drugs. One important reason for this promiscuous behavior of drugs and targets is the limited number of binding sites and the flexibility of drugs. The number of binding sites and drug–target interaction patterns is limited in a similar manner as the number of protein folds is limited. While these numbers of folds and binding sites may be large, they are not infinite. And this implies that there is reuse in nature.
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