DRoP: A Water Analysis Program Identifies Ras-GTP-Specific Pathway of Communication between Membrane-Interacting Regions and the Active Site

Kearney, B.; Johnson, Christian W.; Roberts, Daniel M.; Swartz, Paul; Mattos, Carla

doi:10.1016/j.jmb.2013.10.036

Cited by 39 publications

(64 citation statements)

References 69 publications

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“…This is only one angle on the more general strategy of stabilizing conformational states that may offer windows of opportunity for direct targeting. RAS is full of this type of opportunity throughout its small but complex structure, where intramolecular communication networks between distant sites on the RAS G-domain have been discovered in the past few years (13,(54)(55)(56), but remain largely unexplored. To open new opportunities for drugging RAS, we must understand these structural features in depth, their relative importance in KRAS, NRAS, and HRAS, as well as the ways in which specific mutations at G12, G13, and Q61 affect them in terms of hydrolysis rates and communication with the membrane.…”

Section: The State Of Small Molecules That Directly Bind Rasmentioning

confidence: 99%

Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

Marcus

Mattos

2015

Clinical Cancer Research

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The crystal structure of RAS was first solved 25 years ago. In spite of tremendous and sustained efforts, there are still no drugs in the clinic that directly target this major driver of human cancers. Recent success in the discovery of compounds that bind RAS and inhibit signaling has fueled renewed enthusiasm, and in-depth understanding of the structure and function of RAS has opened new avenues for direct targeting. To succeed, we must focus on the molecular details of the RAS structure and understand at a high-resolution level how the oncogenic mutants impair function. Structural networks of intramolecular communication between the RAS active site and membraneinteracting regions on the G-domain are disrupted in oncogenic mutants. Although conserved across the isoforms, these networks are near hot spots of protein-ligand interactions with amino acid composition that varies among RAS proteins. These differences could have an effect on stabilization of conformational states of interest in attenuating signaling through RAS. The development of strategies to target these novel sites will add a fresh direction in the quest to conquer RAS-driven cancers.

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Section: The State Of Small Molecules That Directly Bind Rasmentioning

confidence: 99%

Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

Marcus

Mattos

2015

Clinical Cancer Research

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“…Lateral segregation is required for correct signaling activity (51), and effector proteins must be able to distinguish between the conformation of GTP-versus GDP-bound Ras with respect to the membrane. This is achieved through conserved nucleotide sensing residues from loop 3 (L3) on the effector lobe and helix 5 on the allosteric lobe near the membrane, providing a common mechanism through which the membrane can sense the state of the nucleotide at the opposite end of the molecule (52,53). Stabilization of the transient orientation of the catalytic domain with respect to the membrane is mediated by residues in the HVR and helix 4 regions of the allosteric lobe, the two regions of the protein that display the highest sequence divergence (9).…”

Section: Nucleotide-induced Changes In Ras-membrane Orientationmentioning

confidence: 99%

“…21, 53). Structures of oncogenic mutants and the Ras/RasGAP complex show an incomplete helix 5 network terminated at N85, indicating a possible override of Ras membrane-dependent communication and signaling regulation (53). An H-Ras surface pocket identified by the multiple solvent crystal structures (MSCS) technique consisting of residues H94, L133, S136, and Y137 (referred to as cluster 2, see Fig.…”

Section: A Structural View Of the Allosteric Lobementioning

confidence: 99%

“…These isoform-specific sequences may have additional impact in protein-membrane interactions. Importantly, they may also influence allosteric lobe-mediated communication between the active site and the membrane, as they are involved in communication networks between the effector and allosteric lobes of Ras (53). For instance, isoform-specific differences can influence the balance of conformational states that link the allosteric and active sites, via helix 3/loop 7 (21), or the water-mediated communication between the nucleotide-sensor residues in helix 5 and the nucleotide binding pocket, via loop 8 and the N-terminal end of helix 3 (53).…”

Section: A Structural View Of the Allosteric Lobementioning

confidence: 99%

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The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain

Parker

Mattos

2015

Molecular Cancer Research

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The small GTPase Ras is mutated in about 20% of human cancers, primarily at active site amino acid residues G12, G13, and Q61. Thus, structural biology research has focused on the active site, impairment of GTP hydrolysis by oncogenic mutants, and characterization of protein-protein interactions in the effector lobe half of the protein. The C-terminal hypervariable region has increasingly gained attention due to its importance in H-Ras, N-Ras, and K-Ras differences in membrane association. A highresolution molecular view of the Ras-membrane interaction involving the allosteric lobe of the catalytic domain has lagged behind, although evidence suggests that it contributes to isoform specificity. The allosteric lobe has recently gained interest for harboring potential sites for more selective targeting of this elusive "undruggable" protein. The present review reveals critical insight that isoform-specific differences appear prominently at these potentially targetable sites and integrates these differences with knowledge of Ras plasma membrane localization, with the intent to better understand the structure-function relationships needed to design isoform-specific Ras inhibitors. Mol Cancer Res; 13(4); 595-603. Ó2015 AACR.

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“…Intriguingly, a conserved water-mediated hydrogen-bonding network linking the nucleotide sensor residues R161 and R164 on helix 5 to the active site was discovered in Ras-GTP but not in Ras-GDP. 85 This hydrogen-bonding network might relay the conformational changes induced by nucleotide binding to helix 5 and subsequently to the directly linked HVR. In this way, the nucleotideinduced conformational changes can affect membrane binding, dimerization and clustering of Ras.…”

Section: Ras Dimerization Oligomerization and Clusteringmentioning

confidence: 99%

Plasma membrane regulates Ras signaling networks

et al. 2015

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DRoP: A Water Analysis Program Identifies Ras-GTP-Specific Pathway of Communication between Membrane-Interacting Regions and the Active Site

Cited by 39 publications

References 69 publications

Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain

Plasma membrane regulates Ras signaling networks

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