8OSN

GTPASE HRAS IN COMPLEX WITH ZN-CYCLEN AT AMBIENT PRESSURE

Summary for 8OSN

• Entry DOI: 10.2210/pdb8osn/pdb
• Related: 8OSM 8OSO
• Descriptor: GTPase HRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: g protein, signaling protein, hpmx, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 19571.86

Authors

Colloc'h, N.,Prange, T.,Girard, E.,Kalbitzer, H.R. (deposition date: 2023-04-19, release date: 2024-05-08, Last modification date: 2024-07-03)

Primary citation

Girard, E.,Lopes, P.,Spoerner, M.,Dhaussy, A.C.,Prange, T.,Kalbitzer, H.R.,Colloc'h, N.
High Pressure Promotes Binding of the Allosteric Inhibitor Zn 2+ -Cyclen in Crystals of Activated H-Ras.
Chemistry, 30:e202400304-e202400304, 2024

PubMed Abstract: 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 small GTPases cycling between active GTP-bound and inactive GDP-bound states. Various states of GTP-bound 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-cyclen is an allosteric inhibitor of Ras protein, designed to bind specifically to the state 1. In H-Ras(wt).Mg.GppNHp crystals soaked with Zn-cyclen, no binding could be observed, as expected in the state 2 conformation which is the dominant state at ambient pressure. Interestingly, Zn-cyclen binding 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 Zn-cyclen to H-Ras can thus be fully characterized 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 in proteins that are in low-populated conformations at ambient conditions, enabling the design of specific inhibitors.

PubMed: 38647362
DOI: 10.1002/chem.202400304

Experimental method

X-RAY DIFFRACTION (1.8 Å)