6FA3
Antibody derived (Abd-6) small molecule binding to KRAS.
Summary for 6FA3
| Entry DOI | 10.2210/pdb6fa3/pdb |
| Related | 5OCG 5OCO 5OCT 6F76 |
| Descriptor | GTPase KRas, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total) |
| Functional Keywords | abd-4, inhibitor, kras, oncoprotein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 122903.84 |
| Authors | Quevedo, C.E.,Cruz-Migoni, A.,Ehebauer, M.T.,Carr, S.B.,Phillips, S.E.V.,Rabbitts, T.H. (deposition date: 2017-12-15, release date: 2018-08-22, Last modification date: 2024-10-16) |
| Primary citation | Quevedo, C.E.,Cruz-Migoni, A.,Bery, N.,Miller, A.,Tanaka, T.,Petch, D.,Bataille, C.J.R.,Lee, L.Y.W.,Fallon, P.S.,Tulmin, H.,Ehebauer, M.T.,Fernandez-Fuentes, N.,Russell, A.J.,Carr, S.B.,Phillips, S.E.V.,Rabbitts, T.H. Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat Commun, 9:3169-3169, 2018 Cited by PubMed Abstract: Targeting specific protein-protein interactions (PPIs) is an attractive concept for drug development, but hard to implement since intracellular antibodies do not penetrate cells and most small-molecule drugs are considered unsuitable for PPI inhibition. A potential solution to these problems is to select intracellular antibody fragments to block PPIs, use these antibody fragments for target validation in disease models and finally derive small molecules overlapping the antibody-binding site. Here, we explore this strategy using an anti-mutant RAS antibody fragment as a competitor in a small-molecule library screen for identifying RAS-binding compounds. The initial hits are optimized by structure-based design, resulting in potent RAS-binding compounds that interact with RAS inside the cells, prevent RAS-effector interactions and inhibit endogenous RAS-dependent signalling. Our results may aid RAS-dependent cancer drug development and demonstrate a general concept for developing small compounds to replace intracellular antibody fragments, enabling rational drug development to target validated PPIs. PubMed: 30093669DOI: 10.1038/s41467-018-05707-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
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