{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:49:23Z","timestamp":1792406963494,"version":"4.4.0"},"reference-count":45,"publisher":"American Chemical Society (ACS)","license":[{"start":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:00:00Z","timestamp":1792368000000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA25862"],"award-info":[{"award-number":["R01 CA25862"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006518","name":"University of Nebraska Medical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006518","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000138","name":"U.S. Department of Education","doi-asserted-by":"publisher","award":["P200A210032"],"award-info":[{"award-number":["P200A210032"]}],"id":[{"id":"10.13039\/100000138","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM157097"],"award-info":[{"award-number":["R35GM157097"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Geranylgeranyl diphosphate synthase (GGDPS) catalyzes the condensation reaction between two isoprenoid substrates: farnesyl diphosphate (FDP) and isopentenyl pyrophosphate (IPP), to form geranylgeranyl diphosphate (GGDP). Due to the flexible nature of the GGDPS active site and its capacity to bind multiple ligands during the reaction coordinate, understanding the structural changes that enable it to accommodate different ligands and catalyze the reaction is essential. While structures exist of substrate and product-bound GGDPS, a lack of high-resolution apo or Mg2+-only structures prevents complete understanding of the enzyme active site. Here, we report apo and Mg2+-only structures of human GGDPS, investigating the key differences between them and published GGDPS structures relating to the enzymatic cycle. A crystal structure resolved to 1.82 \u00c5, the highest-resolution structure of human GGDPS to date, contains five product-bound subunits and one Mg2+-only subunit. The first cryo-EM structure of apo GGDPS is also reported, which exhibited an open hexamer conformation. Comparing the Mg2+-only and apo structures shows that the active site is posed and ready to bind Mg2+ without significant conformational changes. Comparing Mg2+-only to structures with either of the substrates or product bound, we observe changes in residues that actively obstruct or encourage the binding of certain ligands. We also propose an enzymatic mechanism for the structural states of GGDPS and highlight the possibility of Asp188 as the general base in the condensation reaction. These findings enhance our understanding of GGDPS ligand binding, which will improve the knowledge base for rational, structure-based design of future GGDPS inhibitors.<\/jats:p>","DOI":"10.1021\/acs.biochem.6c00411","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:01:41Z","timestamp":1792144901000},"source":"Crossref","is-referenced-by-count":0,"title":["Mapping Ligand-Induced Conformational Changes during\nthe Enzymatic Cycle of Human Geranylgeranyl Diphosphate Synthase"],"prefix":"10.1021","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7901-9746","authenticated-orcid":true,"given":"Andrew C.","family":"Pham","sequence":"first","affiliation":[{"name":"University of Nebraska Medical Center , , , ,","place":["Omaha, Nebraska, United States, 68198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas R.","family":"Struble","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , ,","place":["Omaha, Nebraska, United States, 68198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasini","family":"Amunugama","sequence":"additional","affiliation":[{"name":"University of Nebraska-Lincoln , , , ,","place":["Lincoln, Nebraska, United States, 68588"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1130-1728","authenticated-orcid":true,"given":"Jared B.","family":"Shaw","sequence":"additional","affiliation":[{"name":"University of Nebraska-Lincoln , , , ,","place":["Lincoln, Nebraska, United States, 68588"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6097-4857","authenticated-orcid":true,"given":"Timothy R.","family":"Stachowski","sequence":"additional","affiliation":[{"name":"St. Jude Children\u2019s Research Hospital , , , ,","place":["Memphis, Tennessee, United States, 38105"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9342-5635","authenticated-orcid":true,"given":"Sarah A.","family":"Holstein","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , ,","place":["Omaha, Nebraska, United States, 68198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8070-0258","authenticated-orcid":true,"given":"Gloria E.O.","family":"Borgstahl","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , ,","place":["Omaha, Nebraska, United States, 68198"]},{"name":"University of Nebraska Medical Center , , , ,","place":["Omaha, Nebraska, United States, 68198"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"2026101906065718200_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527609949","volume-title":"Terpenes:\nflavors, Fragrances, Pharmaca, Pheromones","author":"Breitmaier","year":"2006"},{"key":"2026101906065718200_cit2","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1146\/annurev.bi.65.070196.001325","article-title":"Protein prenylation:\nmolecular mechanisms and functional\nconsequences","volume":"65","author":"Zhang","year":"1996","journal-title":"Annu. Rev. Biochem."},{"issue":"2","key":"2026101906065718200_cit3","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nrm.2015.11","article-title":"Protein prenylation:\nunique fats make their mark on\nbiology","volume":"17","author":"Wang","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026101906065718200_cit4","doi-asserted-by":"publisher","first-page":"641188","DOI":"10.3389\/fimmu.2021.641188","article-title":"A Requirement of Protein\nGeranylgeranylation for Chemokine Receptor\nSignaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis","volume":"12","author":"Swan","year":"2021","journal-title":"Front. Immunol."},{"issue":"9","key":"2026101906065718200_cit5","first-page":"1991","article-title":"Protein\ngeranylgeranylation, not farnesylation, is required for the G1 to\nS phase transition in mouse fibroblasts","volume":"13","author":"Vogt","year":"1996","journal-title":"Oncogene"},{"issue":"5","key":"2026101906065718200_cit6","doi-asserted-by":"publisher","first-page":"1882","DOI":"10.1091\/mbc.e02-10-0639","article-title":"Membrane\ntargeting of Rab GTPases\nis influenced by the prenylation motif","volume":"14","author":"Gomes","year":"2003","journal-title":"Mol.\nBiol. Cell"},{"issue":"4","key":"2026101906065718200_cit7","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1007\/s11427-015-4836-1","article-title":"Protein prenylation and human diseases: a balance of protein farnesylation\nand geranylgeranylation","volume":"58","author":"Xu","year":"2015","journal-title":"Sci. China Life Sci."},{"issue":"3","key":"2026101906065718200_cit8","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1124\/jpet.107.132217","article-title":"Inhibition of geranylgeranyl diphosphate synthase induces\napoptosis through multiple mechanisms and displays synergy with inhibition\nof other isoprenoid biosynthetic enzymes","volume":"324","author":"Dudakovic","year":"2008","journal-title":"J.\nPharmacol. Exp. Ther."},{"issue":"1","key":"2026101906065718200_cit9","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/ddr.22012","article-title":"Evaluation\nof geranylgeranyl diphosphate synthase inhibition as a novel strategy\nfor the treatment of osteosarcoma and Ewing sarcoma","volume":"84","author":"Haney","year":"2023","journal-title":"Drug Dev. Res."},{"issue":"11","key":"2026101906065718200_cit10","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1080\/15384047.2016.1219817","article-title":"Targeting protein geranylgeranylation\nslows tumor development in a murine model of prostate cancer metastasis","volume":"18","author":"Reilly","year":"2017","journal-title":"Cancer Biol. Ther."},{"issue":"4","key":"2026101906065718200_cit11","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.leukres.2010.08.008","article-title":"Isoprenoid biosynthetic\npathway inhibition disrupts\nmonoclonal protein secretion and induces the unfolded protein response\npathway in multiple myeloma cells","volume":"35","author":"Holstein","year":"2011","journal-title":"Leuk. Res."},{"issue":"26","key":"2026101906065718200_cit12","doi-asserted-by":"publisher","first-page":"5308","DOI":"10.1038\/s41388-019-0794-6","article-title":"Inhibition of geranylgeranyl diphosphate\nsynthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma","volume":"38","author":"Haney","year":"2019","journal-title":"Oncogene"},{"issue":"2","key":"2026101906065718200_cit13","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1124\/jpet.119.258624","article-title":"In Vivo\nEvaluation of Isoprenoid\nTriazole Bisphosphonate Inhibitors of Geranylgeranyl Diphosphate Synthase:\nImpact of Olefin Stereochemistry on Toxicity and Biodistribution","volume":"371","author":"Haney","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"issue":"1","key":"2026101906065718200_cit14","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1167","article-title":"Geranylgeranyl diphosphate\nsynthase: Role in human\nhealth, disease and potential therapeutic target","volume":"13","author":"Muehlebach","year":"2023","journal-title":"Clin. Transl. Med."},{"issue":"7","key":"2026101906065718200_cit15","doi-asserted-by":"publisher","first-page":"563","DOI":"10.2174\/1568009616666151203224603","article-title":"Protein Geranylgeranyltransferase\nType 1 as a Target in Cancer","volume":"16","author":"Ullah","year":"2016","journal-title":"Curr. Cancer Drug\nTargets"},{"issue":"10","key":"2026101906065718200_cit16","doi-asserted-by":"publisher","first-page":"5424","DOI":"10.3390\/ijms23105424","article-title":"Protein Prenyltransferases\nand Their Inhibitors: Structural\nand Functional Characterization","volume":"23","author":"Marchwicka","year":"2022","journal-title":"Int. J. Mol.\nSci."},{"issue":"6","key":"2026101906065718200_cit17","doi-asserted-by":"publisher","first-page":"886","DOI":"10.3390\/molecules22060886","article-title":"Recent Advances\nin the Development of Mammalian Geranylgeranyl Diphosphate Synthase\nInhibitors","volume":"22","author":"Haney","year":"2017","journal-title":"Molecules"},{"issue":"4","key":"2026101906065718200_cit18","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1110\/ps.03519904","article-title":"Substrate\nbinding mode and reaction mechanism of undecaprenyl pyrophosphate\nsynthase deduced from crystallographic studies","volume":"13","author":"Chang","year":"2004","journal-title":"Protein Sci."},{"issue":"2","key":"2026101906065718200_cit19","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1105\/tpc.109.071738","article-title":"Structure of a heterotetrameric geranyl pyrophosphate\nsynthase from mint (Mentha piperita) reveals intersubunit regulation","volume":"22","author":"Chang","year":"2010","journal-title":"Plant Cell"},{"issue":"24","key":"2026101906065718200_cit20","doi-asserted-by":"publisher","first-page":"10022","DOI":"10.1073\/pnas.0702254104","article-title":"Bisphosphonates\ntarget multiple sites in both cis- and trans-prenyltransferases","volume":"104","author":"Guo","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"32","key":"2026101906065718200_cit21","doi-asserted-by":"publisher","first-page":"20561","DOI":"10.1016\/S0021-9258(17)32030-6","article-title":"Purification\nand properties of geranylgeranyl-diphosphate\nsynthase from bovine brain","volume":"269","author":"Sagami","year":"1994","journal-title":"J. Biol. Chem."},{"issue":"31","key":"2026101906065718200_cit22","doi-asserted-by":"publisher","first-page":"22004","DOI":"10.1074\/jbc.M602603200","article-title":"The crystal\nstructure of human geranylgeranyl pyrophosphate synthase reveals a\nnovel hexameric arrangement and inhibitory product binding","volume":"281","author":"Kavanagh","year":"2006","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026101906065718200_cit23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1158\/1535-7163.MCT-23-0358","article-title":"Structural\nInsight into Geranylgeranyl\nDiphosphate Synthase (GGDPS) for Cancer Therapy","volume":"23","author":"Pham","year":"2024","journal-title":"Mol. Cancer Ther."},{"issue":"3","key":"2026101906065718200_cit24","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1124\/mol.116.107326","article-title":"Olefin Isomers of\na Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate\nSynthase","volume":"91","author":"Allen","year":"2017","journal-title":"Mol. Pharmacol."},{"issue":"6","key":"2026101906065718200_cit25","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1124\/mol.118.113670","article-title":"Reduced Activity of\nGeranylgeranyl Diphosphate Synthase Mutant Is Involved in Bisphosphonate-Induced\nAtypical Fractures","volume":"94","author":"Lisnyansky","year":"2018","journal-title":"Mol. Pharmacol."},{"issue":"5","key":"2026101906065718200_cit26","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1124\/mol.119.117499","article-title":"Metal Coordination\nIs Crucial for Geranylgeranyl Diphosphate Synthase-Bisphosphonate\nInteractions: A Crystallographic and Computational Analysis","volume":"96","author":"Lisnyansky","year":"2019","journal-title":"Mol. Pharmacol."},{"issue":"15","key":"2026101906065718200_cit27","doi-asserted-by":"publisher","first-page":"6904","DOI":"10.1021\/acs.jmedchem.8b00886","article-title":"Unraveling\nthe Prenylation-Cancer\nParadox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate\nSynthase (GGPPS) Inhibitors","volume":"61","author":"Lacbay","year":"2018","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026101906065718200_cit28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0317437","article-title":"Engineering dimer mutants of human\ngeranylgeranyl pyrophosphate synthase","volume":"20","author":"Ezekiel","year":"2025","journal-title":"PLoS\nOne"},{"issue":"Pt 2","key":"2026101906065718200_cit29","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"Xds","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr., Sect.\nD"},{"issue":"Pt 2","key":"2026101906065718200_cit30","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive Python-based system\nfor macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta\nCrystallogr., Sect. D"},{"issue":"Pt 12 Pt 1","key":"2026101906065718200_cit31","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: model-building tools for molecular\ngraphics","volume":"60","author":"Emsley","year":"2004","journal-title":"Acta Crystallogr., Sect. D"},{"issue":"Pt 10","key":"2026101906065718200_cit32","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1107\/S0907444909029436","article-title":"electronic Ligand Builder and Optimization\nWorkbench (eLBOW): a tool for ligand coordinate and restraint generation","volume":"65","author":"Moriarty","year":"2009","journal-title":"Acta Crystallogr., Sect. D"},{"issue":"3","key":"2026101906065718200_cit33","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nmeth.4169","article-title":"cryoSPARC: algorithms\nfor rapid unsupervised cryo-EM structure determination","volume":"14","author":"Punjani","year":"2017","journal-title":"Nat. Methods"},{"issue":"11","key":"2026101906065718200_cit34","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX: Tools for structure\nbuilding and analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci."},{"issue":"3","key":"2026101906065718200_cit35","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1038\/s41592-020-0731-1","article-title":"Measurement of atom resolvability\nin cryo-EM maps with Q-scores","volume":"17","author":"Pintilie","year":"2020","journal-title":"Nat. Methods"},{"issue":"3","key":"2026101906065718200_cit36","doi-asserted-by":"publisher","first-page":"2471","DOI":"10.1021\/acs.jmedchem.1c01913","article-title":"Synthesis\nand Evaluation of Structurally Diverse C-2-Substituted Thienopyrimidine-Based\nInhibitors of the Human Geranylgeranyl Pyrophosphate Synthase","volume":"65","author":"Lee","year":"2022","journal-title":"J. Med. Chem."},{"issue":"3","key":"2026101906065718200_cit37","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1093\/jb\/mvm144","article-title":"Human geranylgeranyl diphosphate\nsynthase is an octamer in solution","volume":"142","author":"Miyagi","year":"2007","journal-title":"J. Biochem."},{"issue":"9","key":"2026101906065718200_cit38","doi-asserted-by":"publisher","first-page":"5888","DOI":"10.1074\/jbc.274.9.5888","article-title":"Human geranylgeranyl\ndiphosphate synthase. cDNA cloning and expression","volume":"274","author":"Kuzuguchi","year":"1999","journal-title":"J. Biol. Chem."},{"issue":"21","key":"2026101906065718200_cit39","doi-asserted-by":"publisher","first-page":"5802","DOI":"10.1111\/febs.70181","article-title":"A somatic\nmultiple myeloma mutation unravels a mechanism of oligomerization-mediated\nproduct inhibition in GGPPS","volume":"292","author":"Yehia","year":"2025","journal-title":"Febs J."},{"issue":"25","key":"2026101906065718200_cit40","doi-asserted-by":"publisher","first-page":"5470","DOI":"10.1021\/bi00644a012","article-title":"Mechanism\nof the prenyl-transfer reaction. Studies\nwith (E)- and (Z)-3-trifluoromethyl-2-buten-1-yl pyrophosphate","volume":"16","author":"Poulter","year":"1977","journal-title":"Biochemistry"},{"issue":"20","key":"2026101906065718200_cit41","doi-asserted-by":"publisher","first-page":"7227","DOI":"10.1016\/S0021-9258(17)34489-7","article-title":"Farnesyl\npyrophosphate synthetase.\nMechanistic studies of the 1\u2019-4 coupling reaction with 2-fluorogeranyl\npyrophosphate","volume":"253","author":"Poulter","year":"1978","journal-title":"J. Biol. Chem."},{"issue":"10","key":"2026101906065718200_cit42","doi-asserted-by":"publisher","first-page":"2186","DOI":"10.1046\/j.1432-1033.2003.03583.x","article-title":"An alternative mechanism\nof product chain-length determination in type III geranylgeranyl diphosphate\nsynthase","volume":"270","author":"Hemmi","year":"2003","journal-title":"Eur. J. Biochem."},{"issue":"30","key":"2026101906065718200_cit43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605509113","article-title":"A conserved amino acid\nresidue critical for product and substrate specificity in plant triterpene\nsynthases","volume":"113","author":"Salmon","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026101906065718200_cit44","doi-asserted-by":"publisher","first-page":"612728","DOI":"10.3389\/fchem.2020.612728","article-title":"Phosphonate and\nBisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthases: A Structure-Guided\nPerspective","volume":"8","author":"Park","year":"2021","journal-title":"Front. Chem."},{"issue":"1","key":"2026101906065718200_cit45","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s40164-022-00261-6","article-title":"Geranylgeranyl diphosphate synthase\ninhibitor and proteasome\ninhibitor combination therapy in multiple myeloma","volume":"11","author":"Haney","year":"2022","journal-title":"Exp. Hematol. Oncol."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.biochem.6c00411","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/doi\/10.1021\/acs.biochem.6c00411\/68882000\/acs.biochem.6c00411.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/doi\/10.1021\/acs.biochem.6c00411\/68882000\/acs.biochem.6c00411.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:29:08Z","timestamp":1792405748000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/doi\/10.1021\/acs.biochem.6c00411\/5452483\/Mapping-Ligand-Induced-Conformational-Changes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,16]]},"references-count":45,"URL":"https:\/\/doi.org\/10.1021\/acs.biochem.6c00411","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,16]]}}}