4ZA0

Structure of Human Enolase 2 in complex with Phosphonoacetohydroxamate

Summary for 4ZA0

• Entry DOI: 10.2210/pdb4za0/pdb
• Related: 4ZCW
• Descriptor: Gamma-enolase, MAGNESIUM ION, PHOSPHONOACETOHYDROXAMIC ACID, ... (4 entities in total)
• Functional Keywords: enolase gamma, glycolysis, neuron specific enolase, carbohydrate metabolism, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P09104
• Total number of polymer chains: 2
• Total formula weight: 96705.85

Authors

Leonard, P.G.,Maxwell, D.,Czako, B.,Muller, F.L. (deposition date: 2015-04-13, release date: 2016-04-13, Last modification date: 2023-09-27)

Primary citation

Leonard, P.G.,Satani, N.,Maxwell, D.,Lin, Y.H.,Hammoudi, N.,Peng, Z.,Pisaneschi, F.,Link, T.M.,Lee, G.R.,Sun, D.,Prasad, B.A.,Di Francesco, M.E.,Czako, B.,Asara, J.M.,Wang, Y.A.,Bornmann, W.,DePinho, R.A.,Muller, F.L.
SF2312 is a natural phosphonate inhibitor of enolase.
Nat.Chem.Biol., 12:1053-1058, 2016

PubMed Abstract: Despite being crucial for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analog of PhAH, in which the hydroxamic nitrogen is linked to Cα by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure-based search revealed that our hypothesized backbone-stabilized PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the actinomycete Micromonospora, which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low-nanomolar inhibitor of enolase.

PubMed: 27723749
DOI: 10.1038/nchembio.2195

Experimental method

X-RAY DIFFRACTION (2.31 Å)