4N1Z

Crystal Structure of Human Farnesyl Diphosphate Synthase in Complex with BPH-1222

Summary for 4N1Z

• Entry DOI: 10.2210/pdb4n1z/pdb
• Related: 4GA3
• Descriptor: Farnesyl pyrophosphate synthase, PHOSPHATE ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: alpha fold, synthase, ionization, dephosphorylation, cytosol, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 40676.85

Authors

Liu, Y.L.,Xia, Y.,Zhang, Y.,Verma, I.,Oldfield, E. (deposition date: 2013-10-04, release date: 2014-12-10, Last modification date: 2023-09-20)

Primary citation

Xia, Y.,Liu, Y.L.,Xie, Y.,Zhu, W.,Guerra, F.,Shen, S.,Yeddula, N.,Fischer, W.,Low, W.,Zhou, X.,Zhang, Y.,Oldfield, E.,Verma, I.M.
A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin.
Sci Transl Med, 6:263ra161-263ra161, 2014

PubMed Abstract: Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not been successfully targeted. We describe a combination therapy for treating these malignancies with two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D-induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding proteins) critical for tumor growth and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant nuclear factor κB (NF-κB) activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mammalian target of rapamycin (mTOR) pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.

PubMed: 25411474
DOI: 10.1126/scitranslmed.3010382

Experimental method

X-RAY DIFFRACTION (2.35 Å)