4E1E

Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-hexylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+

Summary for 4E1E

• Entry DOI: 10.2210/pdb4e1e/pdb
• Related: 1YHK 1YHL 1YHM 3IBA 3ICK 3ICM 3ICN 3ICZ 4DWB 4DWG 4DXJ 4DZW
• Descriptor: Farnesyl pyrophosphate synthase, MAGNESIUM ION, [2-(hexylamino)ethane-1,1-diyl]bis(phosphonic acid), ... (6 entities in total)
• Functional Keywords: geranyl transferase, farnesyl pyrophosphate synthase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Trypanosoma cruzi
• Total number of polymer chains: 1
• Total formula weight: 41725.33

Authors

Aripirala, S.,Amzel, L.M.,Gabelli, S.B. (deposition date: 2012-03-06, release date: 2013-01-16, Last modification date: 2023-09-13)

Primary citation

Aripirala, S.,Szajnman, S.H.,Jakoncic, J.,Rodriguez, J.B.,Docampo, R.,Gabelli, S.B.,Amzel, L.M.
Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase.
J.Med.Chem., 55:6445-6454, 2012

PubMed Abstract: Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi , the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC(50) values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.

PubMed: 22715997
DOI: 10.1021/jm300425y

Experimental method

X-RAY DIFFRACTION (2.65 Å)