1KZ8

CRYSTAL STRUCTURE OF PORCINE FRUCTOSE-1,6-BISPHOSPHATASE COMPLEXED WITH A NOVEL ALLOSTERIC-SITE INHIBITOR

Summary for 1KZ8

• Entry DOI: 10.2210/pdb1kz8/pdb
• Descriptor: FRUCTOSE-1,6-BISPHOSPHATASE, 6-O-phosphono-beta-D-fructofuranose, MANGANESE (II) ION, ... (6 entities in total)
• Functional Keywords: hydrolase
• Biological source: Sus scrofa (pig)
• Total number of polymer chains: 2
• Total formula weight: 75576.12

Authors

Wright, S.W.,Carlo, A.A.,Carty, M.D.,Danley, D.E.,Hageman, D.L.,Karam, G.A.,Levy, C.B.,Mansour, M.N.,Mathiowetz, A.M.,McClure, L.D.,Nestor, N.B.,McPherson, R.K.,Pandit, J.,Pustilnik, L.R.,Schulte, G.K.,Soeller, W.C.,Treadway, J.L.,Wang, I.-K.,Bauer, P.H. (deposition date: 2002-02-06, release date: 2002-10-16, Last modification date: 2023-08-16)

Primary citation

Wright, S.W.,Carlo, A.A.,Carty, M.D.,Danley, D.E.,Hageman, D.L.,Karam, G.A.,Levy, C.B.,Mansour, M.N.,Mathiowetz, A.M.,McClure, L.D.,Nestor, N.B.,McPherson, R.K.,Pandit, J.,Pustilnik, L.R.,Schulte, G.K.,Soeller, W.C.,Treadway, J.L.,Wang, I.-K.,Bauer, P.H.
ANILINOQUINAZOLINE INHIBITORS OF FRUCTOSE 1,6-BISPHOSPHATASE BIND AT A NOVEL ALLOSTERIC SITE: SYNTHESIS, IN VITRO CHARACTERIZATION, AND X-RAY CRYSTALLOGRAPHY
J.MED.CHEM., 45:3865-3877, 2002

PubMed Abstract: The synthesis and in vitro structure-activity relationships (SAR) of a novel series of anilinoquinazolines as allosteric inhibitors of fructose-1,6-bisphosphatase (F16Bpase) are reported. The compounds have a different SAR as inhibitors of F16Bpase than anilinoquinazolines previously reported. Selective inhibition of F16Bpase can be attained through the addition of appropriate polar functional groups at the quinazoline 2-position, thus separating the F16Bpase inhibitory activity from the epidermal growth factor receptor tyrosine kinase inhibitory activity previously observed with similar structures. The compounds have been found to bind at a symmetry-repeated novel allosteric site at the subunit interface of the enzyme. Inhibition is brought about by binding to a loop comprised of residues 52-72, preventing the necessary participation of these residues in the assembly of the catalytic site. Mutagenesis studies have identified the key amino acid residues in the loop that are required for inhibitor recognition and binding.

PubMed: 12190310
DOI: 10.1021/jm010496a

Experimental method

X-RAY DIFFRACTION (2 Å)