Abstract
Ras GTPases are membrane-anchored molecular switches that mediate signaling pathways controlling a variety of cellular processes, including cell division and development. Despite their prominent role in many forms of cancer, little is known about the structure of the membrane bound protein or the mechanism and thermodynamics of membrane insertion. The modulation of membrane binding by the catalytic domain is another area of on-going scrutiny. Recent computational and experimental efforts that have begun to shed some light on these issues are the subject of this review. The bulk of the available structural and thermodynamic information on membrane-bound Ras has been obtained by studying peptides derived from the membrane-anchoring regions of N-ras and H-ras proteins. However, those results have been complemented by data, though limited, on the membrane binding of the full-length Ras as well as by predictions about putative communication routes between the GTP-hydrolyzing catalytic domain and the membrane-interacting C-terminus. A tentative mechanistic picture of Ras signaling that is emerging from these studies will be discussed in connection with allostery and implication for the design of selective anti-cancer drugs.
Keywords: Membrane orientation, molecular dynamics, allostery, Ras signaling, lipid-anchor, thermodynamics, dynamics
Current Medicinal Chemistry
Title: Mechanisms of Allostery and Membrane Attachment in Ras GTPases: Implications for Anti-Cancer Drug Discovery
Volume: 17 Issue: 1
Author(s): A. A. Gorfe
Affiliation:
Keywords: Membrane orientation, molecular dynamics, allostery, Ras signaling, lipid-anchor, thermodynamics, dynamics
Abstract: Ras GTPases are membrane-anchored molecular switches that mediate signaling pathways controlling a variety of cellular processes, including cell division and development. Despite their prominent role in many forms of cancer, little is known about the structure of the membrane bound protein or the mechanism and thermodynamics of membrane insertion. The modulation of membrane binding by the catalytic domain is another area of on-going scrutiny. Recent computational and experimental efforts that have begun to shed some light on these issues are the subject of this review. The bulk of the available structural and thermodynamic information on membrane-bound Ras has been obtained by studying peptides derived from the membrane-anchoring regions of N-ras and H-ras proteins. However, those results have been complemented by data, though limited, on the membrane binding of the full-length Ras as well as by predictions about putative communication routes between the GTP-hydrolyzing catalytic domain and the membrane-interacting C-terminus. A tentative mechanistic picture of Ras signaling that is emerging from these studies will be discussed in connection with allostery and implication for the design of selective anti-cancer drugs.
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Gorfe A. A., Mechanisms of Allostery and Membrane Attachment in Ras GTPases: Implications for Anti-Cancer Drug Discovery, Current Medicinal Chemistry 2010; 17 (1) . https://dx.doi.org/10.2174/092986710789957832
DOI https://dx.doi.org/10.2174/092986710789957832 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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