6GQW
KRAS-169 Q61H GPPNHP + CH-1
Summary for 6GQW
| Entry DOI | 10.2210/pdb6gqw/pdb |
| Related | 6GOD 6GOE 6GOF 6GOG 6GOM |
| Descriptor | GTPase KRas, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (6 entities in total) |
| Functional Keywords | kras, oncoprotein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 121724.90 |
| Authors | Cruz-Migoni, A.,Quevedo, C.E.,Carr, S.B.,Phillips, S.E.V.,Rabbitts, T.H. (deposition date: 2018-06-08, release date: 2019-02-06, Last modification date: 2024-01-17) |
| Primary citation | Cruz-Migoni, A.,Canning, P.,Quevedo, C.E.,Bataille, C.J.R.,Bery, N.,Miller, A.,Russell, A.J.,Phillips, S.E.V.,Carr, S.B.,Rabbitts, T.H. Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. Proc. Natl. Acad. Sci. U.S.A., 116:2545-2550, 2019 Cited by PubMed Abstract: The gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein-protein interactions. We have refined crystallization conditions for KRAS-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein-protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein-protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein-protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules. PubMed: 30683716DOI: 10.1073/pnas.1811360116 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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