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Ras proteins are small GTPases cycling between active GTP\u2010bound and inactive GDP\u2010bound states. Various states of GTP\u2010bound Ras in active conformation coexist in solution, amongst them, state 2 which binds to effectors, and state 1, weakly populated at ambient conditions, which has a low affinity for effectors. Zn<jats:sup>2+<\/jats:sup>\u2010cyclen is an allosteric inhibitor of Ras protein, designed to bind specifically to the state 1. In H\u2010Ras(wt).Mg<jats:sup>2+<\/jats:sup>.GppNHp crystals soaked with Zn<jats:sup>2+<\/jats:sup>\u2010cyclen, no binding could be observed, as expected in the state 2 conformation which is the dominant state at ambient pressure. Interestingly, Zn<jats:sup>2+<\/jats:sup>\u2010cyclen binding is observed at 500\u2005MPa pressure, close to the nucleotide, in Ras protein that is driven by pressure to a state 1 conformer. The unknown binding mode of Zn<jats:sup>2+<\/jats:sup>\u2010cyclen to H\u2010Ras can thus be fully characterized in atomic details. As a more general conjunction from our study, high pressure x\u2010ray crystallography turns out to be a powerful method to induce transitions allowing drug binding in proteins that are in low\u2010populated conformations at ambient conditions, enabling the design of specific inhibitors.<\/jats:p>","DOI":"10.1002\/chem.202400304","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T09:29:30Z","timestamp":1713778170000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["High Pressure Promotes Binding of the Allosteric Inhibitor Zn<sup>2+<\/sup>\u2010Cyclen in Crystals of Activated H\u2010Ras"],"prefix":"10.1002","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5758-6095","authenticated-orcid":false,"given":"Eric","family":"Girard","sequence":"first","affiliation":[{"name":"CEA CNRS IBS Univ. 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