Dataset Information

Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 6-phosphate, AMP, and magnesium.

ABSTRACT: The crystal structure of fructose-1,6-bisphosphatase (EC 3.1.3.11) complexed with fructose 6-phosphate, AMP, and Mg2+ has been solved by the molecular replacement method and refined at 2.5-A resolution to a R factor of 0.215, with root-mean-square deviations of 0.013 A and 3.5 degrees for bond lengths and bond angles, respectively. No solvent molecules have been included in the refinement. This structure shows large quaternary and tertiary conformational changes from the structures of the unligated enzyme or its fructose 2,6-bisphosphate complex, but the secondary structures remain essentially the same. Dimer C3-C4 of the enzyme-fructose 6-phosphate-AMP-Mg2+ complex twists about 19 degrees relative to the same dimer of the enzyme-fructose 2,6-bisphosphate complex if their C1-C2 dimers are superimposed on one another. Nevertheless, many interfacial interactions between dimers of C1-C2 and C3-C4 are conserved after quaternary structure changes occur. Residues of the AMP domain (residues 6-200) show large migrations of C alpha atoms relative to barely significant positional changes of the FBP domain (residues 201-335).

SUBMITTER: Ke HM

PROVIDER: S-EPMC54299 | biostudies-other | 1990 Jul

REPOSITORIES: biostudies-other

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Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 6-phosphate, AMP, and magnesium.

Ke H M HM Zhang Y P YP Lipscomb W N WN

Proceedings of the National Academy of Sciences of the United States of America 19900701 14

The crystal structure of fructose-1,6-bisphosphatase (EC 3.1.3.11) complexed with fructose 6-phosphate, AMP, and Mg2+ has been solved by the molecular replacement method and refined at 2.5-A resolution to a R factor of 0.215, with root-mean-square deviations of 0.013 A and 3.5 degrees for bond lengths and bond angles, respectively. No solvent molecules have been included in the refinement. This structure shows large quaternary and tertiary conformational changes from the structures of the unliga ...[more]

PMID: 2164670

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Project description:The three-dimensional structure of the complex between fructose 1,6-bisphosphatase (EC 3.1.3.11) and the physiological inhibitor beta-D-fructose 2,6-bisphosphate (Fru-2,6-P2), an analogue of the substrate (fructose 1,6-bisphosphate), has been refined at 2.6-A resolution to a residual error (R) factor of 0.171. The rms deviations are 0.012 A and 2.88 degrees from ideal geometries of bond lengths and angles, respectively. The Fru-2,6-P2 occupies the active sites of both polypeptides C1 and C2 in the crystallographic asymmetric unit in the space group P3(2)21. The furanose and 6-phosphate of Fru-2,6-P2 are located at the fructose 6-phosphate site established earlier, and the 2-phosphate binds to the OH of Ser-124, the NH3+ of Lys-274, and the backbone NH of Gly-122 and Ser-123. Backbone displacements of 1 A occur for residues from Asp-121 to Asn-125. Model building of substrate alpha-D-Fru-1,6-P2 based on the binding structure of Fru-2,6-P2 in the active site shows interactions of the 1-phosphate with the backbone NH of Ser-123 and Ser-124. In the AMP sites, density peaks attributed to Fru-2,6-P2 are seen in C1 (and C4) but not in C2 (and C3). This minor binding of Fru-2,6-P2 to AMP sites partially explains the synergistic interaction between AMP and Fru-2,6-P2 and the protection of the AMP site from acetylation in the presence of Fru-2,6-P2. In the synergistic interaction between AMP and Fru-2,6-P2, inhibition of catalytic metal binding by the presence of Fru-2,6-P2 at the active site, and propagation of structural changes over some 28 A along beta-strand B3 from residues 121 to 125 in the active site to Lys-112 and Tyr-113 in the AMP site, as well as movement of helices across the interdimeric interfaces, may affect AMP binding and the subsequent R-to-T transition. In addition, occupancy of Fru-2,6-P2 at the AMP sites of C1 and C4 may favor binding of AMP to the remaining unoccupied AMP sites and thus promote the accompanying quaternary conformational changes.

Project description:Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.

Dataset Information

Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 6-phosphate, AMP, and magnesium.

Publications

Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 6-phosphate, AMP, and magnesium.

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