PMID:15821168
| Citation |
Yang, R, Lee, MC, Yan, H and Duan, Y (2005) Loop conformation and dynamics of the Escherichia coli HPPK apo-enzyme and its binary complex with MgATP. Biophys. J. 89:95-106 |
|---|---|
| Abstract |
Comparison of the crystallographic and NMR structures of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) suggests that the enzyme may undergo significant conformational change upon binding to its first substrate, ATP. Two of the three surface loops (loop 2 and loop 3) accounting for most of the conformational differences appear to be confined by crystal contacts, raising questions about the putative large-scale induced-fit conformational change of HPPK and the functional roles of the conserved side-chain residues on the loops. To investigate the loop dynamics in crystal-free environment, we carried out molecular dynamics and locally enhanced sampling simulations of the apo-enzyme and the HPPK.MgATP complex. Our simulations showed that the crystallographic B-factors underestimated the loop dynamics considerably. We found that the open-conformation of loop 3 in the binary complex is accessible to the apo-enzyme and is the favored conformation in solution phase. These results revise our previous view of HPPK-substrate interactions and the associated functional mechanism of conformational change. The lessons learned here offer valuable structural insights into the workings of HPPK and should be useful for structure-based drug design. |
| Links |
PubMed PMC1366583 Online version:10.1529/biophysj.105.061556 |
| Keywords |
Adenosine Triphosphate/chemistry; Carbon/chemistry; Computer Simulation; Crystallography, X-Ray; Diphosphotransferases/chemistry; Escherichia coli/enzymology; Escherichia coli Proteins/chemistry; Hydrogen Bonding; Ions; Ligands; Magnesium/chemistry; Magnetic Resonance Spectroscopy; Models, Chemical; Models, Molecular; Molecular Conformation; Protein Binding; Protein Conformation; Protein Structure, Secondary; Temperature; Time Factors |
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