SI/II Pocket of Ras: An Opportunity for a Once "Undruggable" Target

Franca, Tanos Celmar Costa; Maddalena, Michael; Kouidmi, Imène; Ayotte, Yann; Islam, Salim Timo ORCID: https://orcid.org/0000-0001-6853-8446 et Laplante, Steven ORCID: https://orcid.org/0000-0003-2835-5789 (2025). SI/II Pocket of Ras: An Opportunity for a Once "Undruggable" Target Acs Omega , vol. 10 , nº 9. pp. 9463-9473. DOI: 10.1021/acsomega.4c10493.

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Résumé

Mutations on the Ras-family of small GTPases are among the most common molecular oncogenic drivers, with the HRas isoform being primarily associated with head-and-neck and genito-urinary cancers. Although once considered "undruggable," recent efforts have identified a structurally conserved surface pocket in the Ras family, designated the SI/II pocket, situated near the binding site of the guanidine exchange factor (GEF) SOS1. The SI/II pocket may represent a potential target site for a pan-Ras drug. A crystal structure representing the native state of GDP-bound HRasG12V was generated to characterize the topology of the SI/II pocket. This native-state structure was employed, together with the published structure of GppNHp-bound HRasG12V in state 1 (PDB ID: 4EFM), as a base for further molecular dynamics simulations exploring the conformational dynamics of the SI/II pocket via four generated synthetic HRas model structures. Our results show that the SI/II pocket is natively inaccessible in GDP-bound HRas yet becomes accessible in state 1 GppNHp-bound HRas systems, an effect that seems to be more evident in the mutated enzyme. This points to the GTP-bound state as a most promising target for Ras inhibitors directed at the SI/II pocket. Occlusion of the SI/II pocket is dictated by the spatial position of the alpha 2 alpha helix in relation to the protein core, with alpha 2 residue Y71 acting as a "tyrosine toggle" capable of restricting the pocket access.

Type de document:	Article
Mots-clés libres:	-
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	17 mars 2025 01:47
Dernière modification:	17 mars 2025 13:33
URI:	https://espace.inrs.ca/id/eprint/16374

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