5TLH

Fructose-1,6-bisphosphate aldolase from rabbit muscle in complex with the inhibitor 2-naphthol 6-bisphosphonate

Summary for 5TLH

• Entry DOI: 10.2210/pdb5tlh/pdb
• Related: 5TLE 5TLW 5TLZ
• Descriptor: Fructose-bisphosphate aldolase A, [(6-hydroxynaphthalen-2-yl)methylene]bis(phosphonic acid), METHYLENEDIPHOSPHONIC ACID, ... (5 entities in total)
• Functional Keywords: inhibitor, bisphosphonate, complex, aldolase, lyase, lyase-inhibitor complex, lyase/inhibitor
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 4
• Total formula weight: 159215.51

Authors

Heron, P.W.,Sygusch, J. (deposition date: 2016-10-11, release date: 2017-10-25, Last modification date: 2023-10-18)

Primary citation

Heron, P.W.,Abellan-Flos, M.,Salmon, L.,Sygusch, J.
Bisphosphonate Inhibitors of Mammalian Glycolytic Aldolase.
J.Med.Chem., 61:10558-10572, 2018

PubMed Abstract: The glycolytic enzyme aldolase is an emerging drug target in diseases such as cancer and protozoan infections which are dependent on a hyperglycolytic phenotype to synthesize adenosine 5'-triphosphate and metabolic precursors for biomass production. To date, structural information for the enzyme in complex with phosphate-derived inhibitors has been lacking. Thus, we determined the crystal structure of mammalian aldolase in complex with naphthalene 2,6-bisphosphate (1) that served as a template for the design of bisphosphonate-based inhibitors, namely, 2-phosphate-naphthalene 6-bisphosphonate (2), 2-naphthol 6-bisphosphonate (3), and 1-phosphate-benzene 4-bisphosphonate (4). All inhibitors targeted the active site, and the most promising lead, 2, exhibited slow-binding inhibition with an overall inhibition constant of ∼38 nM. Compound 2 inhibited proliferation of HeLa cancer cells, whereas HEK293 cells expressing a normal phenotype were not inhibited. The crystal structures delineated the essential features of high-affinity phosphate-derived inhibitors and provide a template for the development of inhibitors with prophylaxis potential.

PubMed: 30418024
DOI: 10.1021/acs.jmedchem.8b01000

Experimental method

X-RAY DIFFRACTION (2.204 Å)