8rdx

From Proteopedia

PGGtase I in complex with probe BAY-6092

Structural highlights

8rdx is a 12 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.67Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PGTB1_RAT Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. Acts on the Rac1, Rac2, Rap1A and Rap1B proteins. The beta subunit is responsible for peptide-binding.

Publication Abstract from PubMed

This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.

Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling.,Graham K, Lienau P, Bader B, Prechtl S, Naujoks J, Lesche R, Weiske J, Kuehnlenz J, Brzezinka K, Potze L, Zanconato F, Nicke B, Montebaur A, Bone W, Golfier S, Kaulfuss S, Kopitz C, Pilari S, Steuber H, Hayat S, Kamburov A, Steffen A, Schlicker A, Buchgraber P, Braeuer N, Font NA, Heinrich T, Kuhnke L, Nowak-Reppel K, Stresemann C, Steigemann P, Walter AO, Blotta S, Ocker M, Lakner A, von Nussbaum F, Mumberg D, Eis K, Piccolo S, Lange M Cell Chem Biol. 2024 Jul 18;31(7):1247-1263.e16. doi: , 10.1016/j.chembiol.2024.02.013. Epub 2024 Mar 26. PMID:38537632^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Graham K, Lienau P, Bader B, Prechtl S, Naujoks J, Lesche R, Weiske J, Kuehnlenz J, Brzezinka K, Potze L, Zanconato F, Nicke B, Montebaur A, Bone W, Golfier S, Kaulfuss S, Kopitz C, Pilari S, Steuber H, Hayat S, Kamburov A, Steffen A, Schlicker A, Buchgraber P, Braeuer N, Font NA, Heinrich T, Kuhnke L, Nowak-Reppel K, Stresemann C, Steigemann P, Walter AO, Blotta S, Ocker M, Lakner A, von Nussbaum F, Mumberg D, Eis K, Piccolo S, Lange M. Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling. Cell Chem Biol. 2024 Jul 18;31(7):1247-1263.e16. PMID:38537632 doi:10.1016/j.chembiol.2024.02.013