2jjk

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FRUCTOSE-1,6-BISPHOSPHATASE(D-FRUCTOSE-1,6-BISPHOSPHATE -1- PHOSPHOHYDROLASE) (E.C.3.1.3.11) COMPLEXED WITH A DUAL BINDING AMP SITE INHIBITOR

Structural highlights

2jjk is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:R15
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

F16P1_HUMAN Defects in FBP1 are the cause of fructose-1,6-bisphosphatase deficiency (FBPD) [MIM:229700. FBPD is inherited as an autosomal recessive disorder mainly in the liver and causes life-threatening episodes of hypoglycemia and metabolic acidosis (lactacidemia) in newborn infants or young children.[1] [2]

Function

F16P1_HUMAN

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Human fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11) is a key gluconeogenic enzyme, responsible for the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, and thus presents an opportunity for the development of novel therapeutics focused on lowering the hepatic glucose production in type 2 diabetics. In its active form FBPase exists as a homotetramer and is allosterically regulated by AMP. In an HTS campaign aromatic sulfonylureas have been identified as FBPase inhibitors mimicking AMP. By bridging two adjacent allosteric binding sites using two aromatic sulfonylureas as anchor units and covalently linking them, it was possible to obtain dual binding AMP site inhibitors that exhibit a strong inhibitory effect.

Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites.,Hebeisen P, Kuhn B, Kohler P, Gubler M, Huber W, Kitas E, Schott B, Benz J, Joseph C, Ruf A Bioorg Med Chem Lett. 2008 Aug 15;18(16):4708-12. Epub 2008 Jul 5. PMID:18650089[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
1 reviews cite this structure
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
Rich et al. (2010)
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16 other articles
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See Also

References

  1. ↑ Kikawa Y, Inuzuka M, Jin BY, Kaji S, Koga J, Yamamoto Y, Fujisawa K, Hata I, Nakai A, Shigematsu Y, Mizunuma H, Taketo A, Mayumi M, Sudo M. Identification of genetic mutations in Japanese patients with fructose-1,6-bisphosphatase deficiency. Am J Hum Genet. 1997 Oct;61(4):852-61. PMID:9382095
  2. ↑ Matsuura T, Chinen Y, Arashiro R, Katsuren K, Tamura T, Hyakuna N, Ohta T. Two newly identified genomic mutations in a Japanese female patient with fructose-1,6-bisphosphatase (FBPase) deficiency. Mol Genet Metab. 2002 Jul;76(3):207-10. PMID:12126934
  3. ↑ Hebeisen P, Kuhn B, Kohler P, Gubler M, Huber W, Kitas E, Schott B, Benz J, Joseph C, Ruf A. Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4708-12. Epub 2008 Jul 5. PMID:18650089 doi:10.1016/j.bmcl.2008.06.103

Contents


PDB ID 2jjk

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OCA

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