Biophysical and Mechanistic Insights into Novel Allosteric Inhibitor of Spleen Tyrosine Kinase

Hall, J. Perry; Aulabaugh, Ann; Rajamohan, Francis; Liu, Shenping; Kaila, Neelu; Wan, Zhengming; Ryan, Mark; Magyar, Rachelle A.; Qiu, Xiayang

doi:10.1074/jbc.m111.311993

Cited by 10 publications

(3 citation statements)

References 51 publications

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“…This is the same mechanism X1 uses to inhibit Syk (spleen tyrosine kinase) (28). The inhibition mechanism has been interrogated using a combination of structural, computational, and kinetic studies, demonstrating that X1 inhibits Syk by reinforcing the natural regulatory interactions between the SH2 and kinase domains and, thus, keeps the enzyme in its inactive conformation.…”

Section: Figurementioning

confidence: 91%

Tyrosine Kinase Inhibitors: Views of Selectivity, Sensitivity, and Clinical Performance

Levitzki

2013

Annu. Rev. Pharmacol. Toxicol.

172

166

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With the manufacture of imatinib, researchers introduced tyrosine kinase inhibitors (TKIs) into the clinical setting in 2000 to treat cancers; approximately fifteen other TKIs soon followed. Imatinib remains the most successful agent, whereas all the others have had modest effects on the cancers that they target. The current challenge is to identify the agents that need to be combined with TKIs to maximize their efficacy. One of the most promising approaches is to combine immune therapy with TKI treatment. In this review, the therapeutic potential of TKIs for treatment is discussed.

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Section: Figurementioning

confidence: 91%

Tyrosine Kinase Inhibitors: Views of Selectivity, Sensitivity, and Clinical Performance

Levitzki

2013

Annu. Rev. Pharmacol. Toxicol.

172

166

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“…SAXS based analyses could screen and/or define unique inhibitors the can inhibit or promote conformational changes (e.g. [92]) and/or assembly formations. Thus, this SAXS-based screening approach could provide new avenue for inhibitor design, avoiding off-target activities that can often occur when targeting enzyme active sites such as kinases.…”

Section: 4 Conclusionmentioning

confidence: 99%

Developing advanced X-ray scattering methods combined with crystallography and computation

Perry

Tainer

2013

Methods

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The extensive use of small angle x-ray scattering (SAXS) over the last few years is rapidly providing new insights into protein interactions, complex formation and conformational states in solution. This SAXS methodology allows for detailed biophysical quantification of samples of interest. Initial analyses provide a judgment of sample quality, revealing the potential presence of aggregation, the overall extent of folding or disorder, the radius of gyration, maximum particle dimensions and oligomerization state. Structural characterizations include ab initio approaches from SAXS data alone, and when combined with previously determined crystal/NMR, atomistic modeling can further enhance structural solutions and assess validity. This combination can provide definitions of architectures, spatial organizations of protein domains within a complex, including those not determined by crystallography or NMR, as well as defining key conformational states of a protein interaction. SAXS is not generally constrained by macromolecule size, and the rapid collection of data in a 96-well plate format provides methods to screen sample conditions. This includes screening for co-factors, substrates, differing protein or nucleotide partners or small molecule inhibitors, to more fully characterize the variations within assembly states and key conformational changes. Such analyses may be useful for screening constructs and conditions to determine those most likely to promote crystal growth of a complex under study. Moreover, these high throughput structural determinations can be leveraged to define how polymorphisms affect assembly formations and activities. This is in addition to potentially providing architectural characterizations of complexes and interactions for systems biology-based research, and distinctions in assemblies and interactions in comparative genomics. Thus, SAXS combined with crystallography/NMR and computation provides a unique set of tools that should be considered as being part of one’s repertoire of biophysical analyses, when conducting characterizations of protein and other macromolecular interactions.

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“…A catalytic domain or SH1 containing 300 amino acids follows the interdomain linker. It contains the binding sites for ATP and two autophosphorylation sites (Tyr525 and Tyr526) [ 9 ]. Syk protein ends with a C-terminal tail, the function of which is currently unidentified.…”

Section: Introductionmentioning

confidence: 99%

Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria

Marchetti

Dessì

Dallocchio

et al. 2020

IJMS

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Resistance to antimalarial drugs has spread rapidly over the past few decades. The WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated malaria, but unfortunately these approaches are losing their efficacy in large areas of Southeast Asia. In 2016, artemisinin resistance was confirmed in 5 countries of the Greater Mekong subregion. We focused our study on Syk inhibitors as antimalarial drugs. The Syk protein is present in human erythrocytes, and the membrane of protein band 3 is its major target following activation by oxidant stress. Tyr phosphorylation of band 3 occurs during P. falciparum growth, leading to the release of microparticles containing hemicromes and structural weakening of the host cell membrane, simplifying merozoite reinfection. Syk inhibitors block these events by interacting with the Syk protein’s catalytic site. We performed in vitro proteomics and in silico studies and compared the results. In vitro studies were based on treatment of the parasite’s cellular cultures with different concentrations of Syk inhibitors, while proteomics studies were focused on the Tyr phosphorylation of band 3 by Syk protein with the same concentrations of drugs. In silico studies were based on different molecular modeling approaches in order to analyze and optimize the ligand–protein interactions and obtain the highest efficacy in vitro. In the presence of Syk inhibitors, we observed a marked decrease of band 3 Tyr phosphorylation according to the increase of the drug’s concentration. Our studies could be useful for the structural optimization of these compounds and for the design of novel Syk inhibitors in the future.

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Biophysical and Mechanistic Insights into Novel Allosteric Inhibitor of Spleen Tyrosine Kinase

Cited by 10 publications

References 51 publications

Tyrosine Kinase Inhibitors: Views of Selectivity, Sensitivity, and Clinical Performance

Tyrosine Kinase Inhibitors: Views of Selectivity, Sensitivity, and Clinical Performance

Developing advanced X-ray scattering methods combined with crystallography and computation

Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria

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