The Distinct Conformational Dynamics of K-Ras and H-Ras A59G

Lukman, Suryani; Grant, Barry J.; Gorfe, Alemayehu A.; Grant, Guy H.; McCammon, J. Andrew

doi:10.1371/journal.pcbi.1000922

Cited by 85 publications

(115 citation statements)

References 43 publications

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“…2. Pocket 1 comprises the effector binding loop (residues [30][31][32][33][34][35][36][37][38][39][40], β2 (residues 55 and 57), and several residues in α-helix 1. Pocket 2 involves the core β-strands 1 and 2, part of the effector loop, and switch 2.…”

Section: Resultsmentioning

confidence: 99%

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Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Hocker

Cho

Chen

et al. 2013

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

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135

133

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Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several smallmolecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)-a bicyclic diterpenoid lactone isolated from Andrographis paniculata-and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.cancer | molecular dynamics | allosteric site | drug design

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Section: Resultsmentioning

confidence: 99%

“…4B). To test whether the ligands stabilize a particular Ras conformation, we used a principal component (PC)-based analysis developed previously (13,(34)(35)(36) to map conformers from K-Ras-SRJ23 trajectories onto a PC plane defined by crystal structures. Fig.…”

Section: Resultsmentioning

confidence: 99%

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Hocker

Cho

Chen

et al. 2013

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

Self Cite

135

133

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“…Molecular dynamics has been previously applied to study various eukaryotic cytoskeletal proteins (19,20). Recently, molecular dynamics simulations revealed nucleotide-induced structural transitions in a subunit of the molecular chaperone GroEL (21) and the signaling protein Ras (22), attesting to the utility of molecular dynamics in studying nucleotide-dependent conformational shifts in proteins. Our simulations demonstrated that GTP-and GDP-bound FtsZ dimers have inherently different conformations and dynamics.…”

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confidence: 99%

Nucleotide-dependent conformations of FtsZ dimers and force generation observed through molecular dynamics simulations

Hsin

Gopinathan

Huang

2012

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

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The bacterial cytoskeletal protein FtsZ is a GTPase that is thought to provide mechanical constriction force via an unidentified mechanism. Purified FtsZ polymerizes into filaments with varying structures in vitro: while GTP-bound FtsZ assembles into straight or gently curved filaments, GDP-bound FtsZ forms highly curved filaments, prompting the hypothesis that a difference in the inherent curvature of FtsZ filaments provides mechanical force. However, no nucleotide-dependent structural transition of FtsZ monomers has been observed to support this force generation model. Here, we present a series of all-atom molecular dynamics simulations probing the effects of nucleotide binding on the structure of an FtsZ dimer. We found that the FtsZ-dimer structure is dependent on nucleotidebinding state. While a GTP-bound FtsZ dimer retained a firm monomer-monomer contact, a GDP-bound FtsZ dimer lost some of the monomer-monomer association, leading to a "hinge-opening" event that resulted in a more bent dimer, while leaving each monomer structure largely unaffected. We constructed models of FtsZ filaments and found that a GDP-FtsZ filament is much more curved than a GTP-FtsZ filament, with the degree of curvature matching prior experimental data. FtsZ dynamics were used to estimate the amount of force an FtsZ filament could exert when hydrolysis occurs (20-30 pN per monomer). This magnitude of force is sufficient to direct inward cell-wall growth during division, and to produce the observed degree of membrane pinching in liposomes. Taken together, our data provide molecular-scale insight on the origin of FtsZ-based constriction force, and the mechanism underlying prokaryotic cell division.bacterial cell division | bacterial cytoskeleton | GTP hydrolysis T he bacterial cell-division protein FtsZ, a tubulin homolog and a GTPase, polymerizes into filaments situated underneath the cytoplasmic membrane at the division site (1-3). The ftsz gene is essential and depletion of FtsZ protein leads to cells unable to divide that instead take on a filamentous morphology (4). During division, rod-shaped bacteria such as Escherichia coli synthesize new hemispherical membrane and cell wall, requiring inward forces. While an array of proteins are needed for division to occur (5, 6), FtsZ alone has been demonstrated to be sufficient for generating inward pinching forces on liposomes in vitro (7-10), and is thought to be the source of the constriction force needed for division.How FtsZ generates mechanical force is still unclear, but several models have been proposed (11), one of which is based on the intrinsic nucleotide-dependent bending of FtsZ filaments (12, 13). In the presence of GTP, purified FtsZ assembles into either straight or gently curved filaments with a radius of curvature of approximately 100 nm, while in the presence of GDP, highly curved filaments form with a radius of curvature of approximately 10 nm (12,14,15). Subsequent theoretical modeling demonstrated that the rapid transition between straight and curved FtsZ filaments...

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“…Also, a computational study on PDZ binding to the BAR domain of PICK1 elucidated by molecular dynamics has been done which details the molecular mechanisms of their binding [13]. Other similar computational studies on protein-ligand interactions have been reported earlier [1,2,22].…”

Section: Introductionmentioning

confidence: 85%

Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study

Saqib

Siddiqi

2011

J Chem Biol

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SRC homology 2 (SH2)-containing inositol 5′-phosphatase protein (SHIP2) is a potential target for type 2 diabetes. Its ability to dephosphorylate the lipid messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], important for insulin signaling, makes it an important target against type 2 diabetes. The insulin-induced SHIP2 interaction with Shc is very important for the membrane localization and functioning of SHIP2. There is a bidentate relationship between the two proteins where two domains each from SHIP2 and Shc are involved in mutual binding. However in the present study, the SHIP2-SH2 domain binding with the phosphorylated tyrosine 317 on the collagen-homology (CH) domain of Shc, has been studied due to the indispensability of this interaction in SHIP2 localization. In the absence of the crystal structure of SHIP2-SH2, its structural model was developed followed by tracking its molecular interactions with Shc through molecular docking and dynamics studies. This study revealed much about the structural interactions between the SHIP2-SH2 and Shc-CH. Finally, docking study of a nonpeptide inhibitor into the SHIP2-SH2 domain further confirmed the structural interactions involved in ligand binding and also proposed the inhibitor as a major starting point against SHIP2-SH2 inhibition. The insights gained from the current study should prove useful in the design of more potent inhibitors against type 2 diabetes.

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The Distinct Conformational Dynamics of K-Ras and H-Ras A59G

Cited by 85 publications

References 43 publications

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Nucleotide-dependent conformations of FtsZ dimers and force generation observed through molecular dynamics simulations

Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study

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