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Geranylgeranyl diphosphate synthase (GGPPS), producing a key prenylation moiety, exists in a dimeric or hexameric form, depending on the species. However, the functional significance of this oligomerization remains unclear. Using crystallography, mass spectrometry, and fluorescence spectroscopy, we show that the GGPPS\n                    <jats:sup>R235C<\/jats:sup>\n                    mutant\u2014found in the widely studied MM cell line RPMI\u20108226\u2014exhibits weakened inter\u2010dimer interactions, reduced hexamer stability, and increased apparent substrate affinity and product release kinetics. These effects are even more pronounced in a dimeric mutant, GGPPS\n                    <jats:sup>Y246D<\/jats:sup>\n                    , demonstrating that interdimer interactions within the hexamer help stabilize a lid region over the active site, thereby stabilizing product binding in an inhibitory conformation. Together, these findings reveal that hexamerization regulates GGPPS activity through product inhibition and underscore the importance of cell line selection and characterization in drug discovery efforts.\n                  <\/jats:p>","DOI":"10.1111\/febs.70181","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T08:00:49Z","timestamp":1751875249000},"page":"5802-5817","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A somatic multiple myeloma mutation unravels a mechanism of oligomerization\u2010mediated product inhibition in\n                    <scp>GGPPS<\/scp>"],"prefix":"10.1111","volume":"292","author":[{"given":"Ruba","family":"Yehia","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Gray Faculty of Medical and Health Sciences Tel\u2010Aviv University  Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasm\u00edna 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