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High pressure promotes binding of the allosteric inhibitor Zn2+‐cyclen in crystals of activated H‐Ras

Chemistry : a European journal, 2024-04 [Peer Reviewed Journal]

Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 0947-6539 ;EISSN: 1521-3765 ;DOI: 10.1002/chem.202400304

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  • Title:
    High pressure promotes binding of the allosteric inhibitor Zn2+‐cyclen in crystals of activated H‐Ras
  • Author: Girard, Eric ; Lopes, Pedro ; Spoerner, Michael ; Dhaussy, Anne-Claire ; Prangé, Thierry ; Kalbitzer, Hans Robert ; Colloc’h, Nathalie
  • Subjects: Life Sciences
  • Is Part Of: Chemistry : a European journal, 2024-04
  • Description: In this work, we experimentally investigate the potency of high pressure to drive a protein toward an excited state where an inhibitor targeted for this state can bind. Ras proteins are smallGTPases cycling between active GTP-bound and inactive GDPbound states. Various states of GTP-bound Ras in active conformation coexist in solution, amongst them, state 2 which bindsto effectors, and state 1, weakly populated at ambient conditions, which has a low affinity for effectors. Zn2+-cyclen is an allosteric inhibitor of Ras protein, designed to bind specifically to the state 1. InH-Ras(wt).Mg2+.GppNHp crystals soaked with Zn2+-cyclen, no binding could be observed, as expected in the state 2 conformation which is the dominant state at ambient pressure. Interestingly, Zn2+-cyclenbinding is observed at 500 MPa pressure, close to the nucleotide, in Ras protein that is driven by pressure to a state 1 conformer. The unknown binding mode of Zn2+-cyclen to H-Ras can thus be fullycharacterized in atomic details. As a more general conjunction from our study, high pressure x-ray crystallography turns out to be a powerful method to induce transitions allowing drug binding inproteins that are in low-populated conformations at ambient conditions, enabling the design of specific inhibitors.
  • Publisher: Wiley-VCH Verlag
  • Language: English
  • Identifier: ISSN: 0947-6539
    EISSN: 1521-3765
    DOI: 10.1002/chem.202400304
  • Source: Hyper Article en Ligne (HAL) (Open Access)
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