5E95: Crystal Structure Of Mb(ns1)/h-ras Complex

RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the alpha4-beta6-alpha5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF-BRAF heterodimerization and activation. These results establish the importance of the alpha4-beta6-alpha5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.
PDB ID: 5E95Download
MMDB ID: 144479
PDB Deposition Date: 2015/10/14
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 1.4  Å
Source Organism:
Similar Structures:
Biological Unit for 5E95: dimeric; determined by author and by software (PISA)
Molecular Components in 5E95
Label Count Molecule
Proteins (2 molecules)
Molecule annotation
Gtpase Hras(Gene symbol: HRAS)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

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