7LGI

The haddock model of GDP KRas in complex with promazine using chemical shift perturbations and intermolecular NOEs

Summary for 7LGI

• Entry DOI: 10.2210/pdb7lgi/pdb
• Related: 6V5L
• NMR Information: BMRB: 30845
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: gdp kras, small molecule ligand, haddock structure model, chemical shift changes, intermolecular noe, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20023.69

Authors

Wang, X.,Gorfe, A.A.,Putkey, J.A. (deposition date: 2021-01-20, release date: 2021-07-21, Last modification date: 2024-05-01)

Primary citation

Wang, X.,Gorfe, A.A.,Putkey, J.A.
Antipsychotic phenothiazine drugs bind to KRAS in vitro.
J.Biomol.Nmr, 75:233-244, 2021

PubMed Abstract: We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild type GppNHp-KRAS. A panel of additional phenothiazines bind to GDP-KRAS but with lower affinity than promazine or promethazine. Binding is most dependent on substitutions at C-2 of the tricyclic phenothiazine ring. Promazine was used to generate an NMR-driven HADDOCK model of the drug/GDP-KRAS complex. The structural model shows the tricyclic phenothiazine ring of promazine associates with the hydrophobic pocket p1 that is bordered by the central β sheet and Switch II in KRAS. Binding appears to stabilize helix 2 in a conformation that is similar to that seen in KRAS bound to other small molecules. Association of phenothiazines with KRAS may affect normal KRAS signaling that could contribute to multiple biological activities of these antipsychotic drugs. Moreover, the phenothiazine ring represents a new core scaffold on which to design modulators of KRAS activity.

PubMed: 34176062
DOI: 10.1007/s10858-021-00371-z

Experimental method

SOLUTION NMR