5HNA

Crystal structure of Plasmodium vivax geranylgeranylpyrophosphate synthase complexed with BPH-1251

Summary for 5HNA

• Entry DOI: 10.2210/pdb5hna/pdb
• Related: 5HN7 5HN8 5HN9
• Descriptor: Farnesyl pyrophosphate synthase, putative, 4-chloro-2-{[3-(decyloxy)-5-hydroxybenzyl]oxy}-5-sulfamoylbenzoic acid (3 entities in total)
• Functional Keywords: transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Plasmodium vivax
• Total number of polymer chains: 4
• Total formula weight: 177192.88

Authors

Liu, Y.-L.,Zhang, Y.,Oldfield, E. (deposition date: 2016-01-18, release date: 2016-09-07, Last modification date: 2023-09-27)

Primary citation

G Ricci, C.,Liu, Y.L.,Zhang, Y.,Wang, Y.,Zhu, W.,Oldfield, E.,McCammon, J.A.
Dynamic Structure and Inhibition of a Malaria Drug Target: Geranylgeranyl Diphosphate Synthase.
Biochemistry, 55:5180-5190, 2016

PubMed Abstract: We report a molecular dynamics investigation of the structure, function, and inhibition of geranylgeranyl diphosphate synthase (GGPPS), a potential drug target, from the malaria parasite Plasmodium vivax. We discovered several GGPPS inhibitors, benzoic acids, and determined their structures crystallographically. We then used molecular dynamics simulations to investigate the dynamics of three such inhibitors and two bisphosphonate inhibitors, zoledronate and a lipophilic analogue of zoledronate, as well as the enzyme's product, GGPP. We were able to identify the main motions that govern substrate binding and product release as well as the molecular features required for GGPPS inhibition by both classes of inhibitor. The results are of broad general interest because they represent the first detailed investigation of the mechanism of action, and inhibition, of an important antimalarial drug target, geranylgeranyl diphosphate synthase, and may help guide the development of other, novel inhibitors as new drug leads.

PubMed: 27564465
DOI: 10.1021/acs.biochem.6b00398

Experimental method

X-RAY DIFFRACTION (2.693 Å)