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Mechanisms of Taste Transduction
Published in Robert H. Cagan, Neural Mechanisms in Taste, 2020
John H. Teeter, Robert H. Cagan
Regulation of many cellular processes, at the molecular level, occurs through allosteric interactions in proteins, which occur between spatially different sites on a protein.63,64 Upon binding of a ligand to one site on the protein, a conformational change results, thereby inducing a change at another site on the protein. The latter change affects the activity at that second site. Classical examples are the regulatory effects upon binding of the ligand, oxygen, to hemoglobin and the binding of cytidine 5′-triphosphate (CTP) to the enzyme aspartate transcarbamylase.
Miscellaneous: Dextran, Dermatan Sulfate, Low Molecular Weight Heparinoids (Org 10172), Pentosan Polysulfate (Sp54), Defibrinating Agents (Ancrod And Reptilase)
Published in Hau C. Kwaan, Meyer M. Samama, Clinical Thrombosis, 2019
M. M. Samama, P. C. Desnoyers, H. C. Kwaan
Their main action is that of converting fibrinogen to fibrin. In contrast to the proteolytic action of thrombin, which results in splitting the arginyl bonds linking the fibrinopeptides A and B, Ancrod and Reptilase release only the fibrinopeptide A from the a chain, while the β and γ chains remain unchanged. A different conformational change then takes place. The thrombin-induced fibrin monomer polymerizes end-to-end as well as side-to-side, but the Ancrod- or Reptilase-induced monomer polymerizes only end-to-end. The resulting polymer produced by thrombin may be expressed as [(αββ)2]n, while that produced by Ancrod or by Reptilase would be {[αβ(B)γ]2}n. Under electron microscopy, these two types of polymers are morphologically different. The thrombin-induced type [(αβγ)2]n fibrin appears as thick, interconnected fibers, while the Ancrod- or Reptilase-induced type {[αβ(B)γ]2}n appears as very thin filaments.
Three-Dimensional Structure of p21 and Its Implications
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
The structures of several different wild-type and mutant p21 complexes have been determined by S. H. Kim and co-workers as well as in our laboratory. A list of the published structures is shown in Table 1 together with the resolutions obtained in the crystallographic analyses. For cellular and one oncogenic mutant p21 both the triphosphate and diphosphate structures have been determined. From these the mechanism of the conformational change could be deduced. For the triphosphate complex of p21 the noncleavable analogs GppNHp and Gpp(CH2)p were used, because GTP and even GTPγS are hydrolyzed by p21 during crystallization. A complex of p21 with a noncleavable GTP analog having a photolabile protecting group on γ-phosphate, which was named cagedGTP, has also been crystallized.32 This latter crystal type was used to determine the three-dimensional structure of the real p21-GTP complex after photolytic cleavage of the protecting group. Additionally, it also allowed us to directly follow the GTP hydrolysis reaction within the crystal and observe the conformational transition from the active to the inactive form of p21.20
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
The functional relevance of this conformational change is supported by a newly discovered small-molecule inhibitor (NSC194308). Identified in high-throughput screening studies, NSC194308 has been proven to bind to the U2AF2/Py-tract complex at the interface of the two RRMs (Figure 3(a)) [64]. NSC194308 inhibits splicing in in vitro assays with an IC50 of ∼35 μM and was shown to exert a brand-new inhibition mechanism [65]. Namely, NSC194308 increased the RNA binding affinity of the U2AF2 and stalled the SPL at an E-like complex by (most likely) interfering with the exchange of the SF1/U2AF2/U2AF1 complex with the U2 snRNP. As a result, NSC194308 preferentially killed the K562 leukemia cell line expressing the U2AF1S34F mutant. This finding is again consistent with the proposition that cancer cells, experiencing a mutant SFs-related splicing burden, are over-sensitive to the drug-induced perturbations. Importantly, NSC194308, enhancing the U2AF2/RNA interaction [66], introduces a novel concept for modulating splicing by promoting (and stalling) SPL assembly.
Unmasking allosteric-binding sites: novel targets for GPCR drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Verònica Casadó-Anguera, Vicent Casadó
The concept of allostery was proposed 60 years ago when the term ‘allosteric inhibition’ was used by Jacques Monod and Francois Jacob to describe a mechanism in which ‘the inhibitor is not a steric analogue of the substrate.’ Allostery consists in ‘an interaction between two topographically distinct sites on an enzyme mediated indirectly by a conformational change’ transmitted between the sites [4]. Shortly after, the mechanism underlying this conformational change was proposed to be the conformational selection. This mechanism predicts that the macromolecule exists in a thermal equilibrium between active and inactive states that can be stabilized by the binding of orthosteric or allosteric ligands to their respective (non-overlapping) binding sites [5]. This mechanism is commonly known as the concerted MWC model by Monod, Wyman, and Changeux [6]. According to this concerted model, different protomers (dimers, tetramers, …) can exist in two different states in equilibrium: a tense (T) state, which has low affinity for the ligand and is the most abundant in its absence, and a relaxed (R) state, which has high affinity for the ligand. All protomers must be in the same state at any time and ligand binding induces a concerted change of conformation of all protomers. Thus, according to this model, all protomers must be in the same conformation and symmetry has to be conserved. The oligomeric nature of the model is also able to explain the phenomenon of positive cooperativity in ligand binding, since the same ligand can bind to different protomers within the oligomer [5].
Unveiling Taenia solium kinome profile and its potential for new therapeutic targets
Published in Expert Review of Proteomics, 2020
Naina Arora, Anand Raj, Farhan Anjum, Rimanpreet Kaur, Suraj Singh Rawat, Rajiv Kumar, Shweta Tripathi, Gagandeep Singh, Amit Prasad
Tyrosine kinases are classified as receptor tyrosine kinase and cytoplasmic tyrosine kinase based on the presence or absence of transmembrane domains. It is the third most abundant kinase in T. solium with 34 sequences; representing six receptor kinase families and nine cytoplasmic kinase families (supplementary 7). The receptor tyrosine kinases are involved in transmembrane signaling; the signaling is mediated by three domains present: extracellular domain, transmembrane domain, and an intracellular domain which carries catalytic center. On ligand binding, the receptor dimerizes and undergoes conformational change that relays signaling. This class consists of EGFR, FGFR, InsR, etc., which participate in growth, development, and metabolism [53]. On the contrary, cytoplasmic tyrosine kinases are involved in signaling to nucleus.