6GOG

KRAS-169 Q61H GPPNHP

Summary for 6GOG

• Entry DOI: 10.2210/pdb6gog/pdb
• Related: 6GOD 6GOE 6GOF
• Descriptor: GTPase KRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kras, oncoprotein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 122519.22

Authors

Cruz-Migoni, A.,Quevedo, C.E.,Carr, S.B.,Phillips, S.V.E.,Rabbitts, T.H. (deposition date: 2018-06-01, 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

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: 30683716
DOI: 10.1073/pnas.1811360116

Experimental method

X-RAY DIFFRACTION (2.05 Å)