3HXB: Engineered Rabggtase In Complex With A Peptidomimetic Inhibitor (compound 6)

Rab geranylgeranyl transferase (RabGGTase) catalyzes the attachment of geranylgeranyl isoprenoids to Rab guanine triphosphatases, which are key regulators in vesicular transport. Because geranylgeranylation is required for proper function and overexpression of Rabs has been observed in various cancers, RabGGTase may be a target for novel therapeutics. The development of selective inhibitors is, however, difficult because two related enzymes involved in other cellular processes exist in eukaryotes and because RabGGTase recognizes protein substrates indirectly, resulting in relaxed specificity. We report the synthesis of a peptidic library based on the farnesyl transferase inhibitor pepticinnamin E. Of 469 compounds investigated, several were identified as selective for RabGGTase with low micromolar IC(50) values. The compounds were not generally cytotoxic and inhibited Rab isoprenylation in COS-7 cells. Crystal structure analysis revealed that selective inhibitors interact with a tunnel unique to RabGGTase, implying that this structural motif is an attractive target for improved RabGGTase inhibitors.
PDB ID: 3HXBDownload
MMDB ID: 76590
PDB Deposition Date: 2009/6/20
Updated in MMDB: 2009/12
Experimental Method:
x-ray diffraction
Resolution: 2.25  Å
Source Organism:
Similar Structures:
Biological Unit for 3HXB: dimeric; determined by author and by software (PISA)
Molecular Components in 3HXB
Label Count Molecule
Proteins (2 molecules)
Geranylgeranyl Transferase Type-2 Subunit Alpha(Gene symbol: Rabggta)
Molecule annotation
Geranylgeranyl Transferase Type-2 Subunit Beta(Gene symbol: Rabggtb)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB