Effect of Polarizability on the Potential of Mean Force of Two Cations. The Guanidinium−Guanidinium Ion Pair in Water

Soetens, Jean-Christophe; Millot, Claude; Chipot, Christophe; Jansen, Georg; Ángyán, János G.; Maigret, Bernard

doi:10.1021/jp972113j

Cited by 79 publications

(123 citation statements)

References 53 publications

(65 reference statements)

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“…Glu-252 and Arg-73 are partially solvent-exposed and have the weakest side chain densities, whereas Arg-71 is almost completely buried and has a strong side chain density (supplemental Table 1). Arg-71 stacks against Arg-71Ј, as observed in other systems (43,44) while interacting with Glu-252 and Glu-252Ј at the LC7 2-fold axis (Fig. 3c).…”

Section: Resultssupporting

confidence: 72%

The Crystal Structure of Dynein Intermediate Chain-Light Chain Roadblock Complex Gives New Insights into Dynein Assembly

Hall

Song

Karplus

et al. 2010

Journal of Biological Chemistry

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The roadblock/LC7 dynein light chain is a ubiquitous component of all dyneins and is essential for many diverse processes including proper axonal transport and dendrite growth. In addition, LC7 functions in non-dynein transcriptional activation of the transforming growth factor-␤ complex. Crystal structures of Drosophila melanogaster LC7 in the apo form and in complex with a segment of the disordered N-terminal domain of dynein intermediate chain (IC) provide the first definitive identification of the IC sequence recognized by LC7. The site, confirmed by isothermal titration calorimetry studies, overlaps the IC sequence considered in the literature to be an IC self-association domain. The IC peptide binds as two amphipathic helices that lie along an extensive hydrophobic cleft on LC7 and ends with a polar side-chain interaction network that includes conserved residues from both proteins. The LC7 recognition sequence on IC and its interface with LC7 are well conserved and are, thus, likely representative of all IC⅐LC7 structures. Interestingly, the position of bound IC in the IC⅐LC7 complex mimics a helix that is integrated into the primary structure in distantly related LC7 homologs. The IC⅐LC7 structure further shows that the naturally occurring robl Z deletion mutation contains the majority of the IC binding site and suggests that promotion of IC binding by phosphorylation of LC7 is an indirect effect.Cytoplasmic dyneins are large multisubunit protein complexes that are responsible for ATP-driven transport of diverse cargo along microtubules. They play fundamental roles within the cell including mitotic spindle assembly and orientation (1), chromosome segregation (2), and intracellular trafficking of vesicles and mRNA (3). Dyneins are essential for the development and maintenance of neurons (4), and dynein dysfunction is associated with several human diseases, such as lissencephaly (5), neural degeneration (6), and male infertility (7).Dynein heavy chains are responsible for motor activity, whereas intermediate chain (IC) 2 and light chain subunits comprise the cargo attachment complex. The N-and C-terminal domains of IC are structurally and functionally independent. The primarily disordered N-terminal domain (N-IC) is central to dynein assembly, regulation, and cargo binding as it contains a self-association domain and the binding sites for the three light chains, the p150 Glued subunit of dynactin, and several putative cargoes (8 -11). Dynein light chains Tctex1, LC8, and LC7 are all integral components of both cytoplasmic and axonemal dyneins (12) that bind distinct regions of N-IC (13, 14) (Fig. 1). Tctex1 and LC8 are dimeric structural homologs, and each binds two chains of IC at its dimer interface (15-17). Tctex1 and LC8 show mutually enhanced affinity, as one protein binds two IC chains to form a bivalent IC that has higher affinity for the other light chain (17). This led to the proposal that Tctex1 and LC8 work together to create a poly-bivalent IC duplex that serves as a stable and versatile scaffol...

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Section: Resultssupporting

confidence: 72%

The Crystal Structure of Dynein Intermediate Chain-Light Chain Roadblock Complex Gives New Insights into Dynein Assembly

Hall

Song

Karplus

et al. 2010

Journal of Biological Chemistry

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“…Instead, R1948 of the mutant kinase reorients toward the ATP binding site, forming an unusual ion-pair with R2032 that restricts P-loop flexibility. This interaction, although uncommon, has also been observed in other proteins as a stabilizing factor (26)(27)(28).…”

Section: Resultsmentioning

confidence: 55%

Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

Davare

Vellore

Wagner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1-and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1 G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1-and ALK-driven NSCLC and other malignancies.onstitutively activated kinase fusion proteins that arise from somatic chromosomal rearrangements are frequent drivers of malignant transformation in cancer and represent a targetable vulnerability for clinical intervention. The clinical success of the tyrosine kinase inhibitor (TKI) imatinib in targeting the oncogenic BCR-ABL1 fusion protein in chronic myeloid leukemia (CML) motivated efforts to identify and target oncogenic kinases in other cancers (1-3). One such setting is non-small cell lung cancer (NSCLC), where chromosomal rearrangements of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) are found in 4-5% of patients (4, 5). The validation of rearranged ALK as an oncogenic driver prompted the discovery and clinical implementation of crizotinib as the first clinical targeted inhibitor for use in ALK fusionpositive NSCLC (6, 7).Fusion proteins involving the highly related kinase ROS1, an orphan RTK of the insulin receptor family, are present in ∼1% of NSCLC patients. ROS1 rearrangements span a variety of fusion partners across several other epithelial malignancies, including cholangiocarcinoma, gastric cancer, and ovarian cancer (4, 8). CD74-ROS1 is the most frequent ROS1 fusion detected in NSCLC. ROS1 fusion proteins are transforming drivers that contribute to tumorigenesis or tumor progression in multiple experimental model systems (9)(10)(11).Approximately 75,000 and 15,000 new NSCLC patients per year are anticipated to harbor tumors...

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“…Calculations by Soetens et al on the interaction between unmethylated guanidinium ions and water showed that a water molecule binds more strongly in the pocket between two neighboring NH groups on a guanidinium ion than to a single NH donor. [40] Our own calculations reveal the presence of such pockets in guanidinium (three pockets; Figure 4a), methylguanidinium (two pockets; Figure 4b), and both dimethylguanidinium ions (one pocket; Figure 4c conformations. This suggests that dimethylation of Arg reduces the strength of hydration by lowering the charge density, and may also have a structural ability to decrease the hydrogen-bonding ability of methylated Arg side chain.…”

Section: H T U N G T R E N N U N G (H 2 O) M ]mentioning

confidence: 86%

Insights into the Post‐Translational Methylation of Arginine from Studies of Guanidinium–Water Nanodroplets

McQuinn

McIndoe

Hof

2008

Chemistry A European J

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Highly solvated methylated guanidinium ions ([Me nGuan(H2O)m](+); n=0-4 and 6; m=1->50), which model the various post-translationally methylated states of arginine, were generated in the electrospray ionization (ESI) source of an unmodified commercial tandem mass spectrometer. The dehydration processes of highly solvated [Me nGuan(H2O)21](+) ions were monitored by using energy-dependent ESI MS. These data, together with supporting calculations, provide a detailed picture of the interplay of methylation and hydration, and both the calculations and the experimental evidence suggest a specific structural basis for the observed effects. The ramifications for biochemical binding events that are controlled by the post-translational methylation of arginine to give dimethylarginines are discussed.

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Effect of Polarizability on the Potential of Mean Force of Two Cations. The Guanidinium−Guanidinium Ion Pair in Water

Cited by 79 publications

References 53 publications

The Crystal Structure of Dynein Intermediate Chain-Light Chain Roadblock Complex Gives New Insights into Dynein Assembly

The Crystal Structure of Dynein Intermediate Chain-Light Chain Roadblock Complex Gives New Insights into Dynein Assembly

Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

Insights into the Post‐Translational Methylation of Arginine from Studies of Guanidinium–Water Nanodroplets

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