Plasticity of CYP2B Enzymes: Structural and Solution Biophysical Methods

Wilderman, P. Ross; Halpert, James R.
February 2012
Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p167
Academic Journal
In the past three years, major advances in understanding cytochrome P450 2B (CYP2B) structure-function relationships have been made through determination of multiple ligand-bound and one ligand-free X-ray crystal structure of CYP2B4 and one ligand-bound X-ray crystal structure of CYP2B6. These structures have provided insight into the features that provide the high degree of plasticity of the enzymes. A combination of a phenylalanine cluster that allows for concerted movement of helices F through G and a conserved set of electrostatic interactions involving Arg262 facilitates movement of this region to accommodate binding of ligands of various sizes without perturbing most of the P450 fold. Integrating solution based techniques such as NMR or deuterium exchange mass spectrometry (DXMS) with computational methods including molecular docking has provided further insight into enzyme behavior upon ligand binding. In addition, extended molecular dynamics simulations have provided a link between an open and a closed conformation of ligand-free CYP2B4 found in crystal structures. Other studies revealed the utility of rational engineering in improving stability of P450s to facilitate structural studies. The solution and computational results combined with the X-ray crystal structures yield a comprehensive picture of how these enzymes adopt different conformations to bind various ligands.


Related Articles

  • Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations. Oostenbrink, Chris; De Ruiter, Anita; Hritz, Jozef; Vermeulen, Nico // Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p190 

    As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show...

  • The Role of Protein Plasticity in Computational Rationalization Studies on Regioselectivity in Testosterone Hydroxylation by Cytochrome P450 BM3 Mutants. De Beer, Stephanie B. A.; Van Bergen, Laura A. H.; Keijzer, Karlijn; Rea, Vanina; Venkataraman, Harini; Guerra, Célia Fonseca; Bickelhaupt, F. Matthias; Vermeulen, Nico P.E.; Commandeur, Jan N.M.; Geerke, Daan P. // Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p155 

    Recently, it was found that mutations in the binding cavity of drug-metabolizing Cytochrome P450 BM3 mutants can result in major changes in regioselectivity in testosterone (TES) hydroxylation. In the current work, we report the intrinsic reactivity of TES' C-H bonds and our attempts to...

  • Human Dipeptidyl Peptidase III: the Role of Asn406 in Ligand Binding and Hydrolysis. Špoljarić, Jasminka; Tomić, Antonija; Vukelić, Bojana; Salopek-Sondi, Branka; Agić, Dejan; Tomić, Sanja; Abramić, Marija // Croatica Chemica Acta;Sep2011, Vol. 84 Issue 2, p259 

    Human dipeptidyl peptidase III (DPP III) is a member of the zinc-metallopeptidase family M49 with a role in intracellular protein catabolism. Ligand-free crystal structure of yeast and human orthologues provided insight into the enzyme's active center and enabled some assumptions about the...

  • Molecular modeling and identification of substrate binding site of orphan human cytochrome P450 4F22. Kumar, Suresh // Bioinformation;2011, Vol. 7 Issue 4, p207 

    Cytochrome P450s are superfamily of heme proteins which generally monooxygenate hydrophobic compounds. The human cytochrome P450 4F22 (CYP4F22) was categorized into "orphan" CYPs because of its unknown function. CYP4F22 is a potential drug target for cancer therapy. However, three-dimensional...

  • Multiple, Ligand-dependent Routes from the Active Site of Cytochrome P450 2C9. Cojocaru, Vlad; Winn, Peter J.; Wade, Rebecca C. // Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p143 

    The active site of liver-specific, drug-metabolizing cytochrome P450 (CYP) monooxygenases is deeply buried in the protein and is connected to the protein surface through multiple tunnels, many of which were found open in different CYP crystal structures. It has been shown that different tunnels...

  • Identification of Selectivity Determinants in CYP Monooxygenases by Modelling and Systematic Analysis of Sequence and Structure. Seifert, Alexander; Pleiss, Jürgen // Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p197 

    Cytochrome P450 monooxygenases (CYPs) form a large, ubiquitous enzyme family and are of great interest in red and white biotechnology. To investigate the effect of protein structure on selectivity, the binding of substrate molecules near to the active site was modelled by molecular dynamics...

  • Identifying ligand binding sites and poses using GPU-accelerated Hamiltonian replica exchange molecular dynamics. Wang, Kai; Chodera, John; Yang, Yanzhi; Shirts, Michael // Journal of Computer-Aided Molecular Design;Dec2013, Vol. 27 Issue 12, p989 

    We present a method to identify small molecule ligand binding sites and poses within a given protein crystal structure using GPU-accelerated Hamiltonian replica exchange molecular dynamics simulations. The Hamiltonians used vary from the physical end state of protein interacting with the ligand...

  • Effect of the structural characteristics of dihydrofolate reductase inhibitors on their metabolic properties. Afon'kina, E.; Pal'ko, N.; Matveev, G.; Toreeva, N.; Potemkin, V.; Grishina, M. // Journal of Structural Chemistry;Mar2012, Vol. 53 Issue 2, p365 

    The orientation of dihydropyrimidine derivatives containing podand chains is determined in the model receptor using the CiS algorithm. The orientation of compounds with podand chains is compared with the location of compounds without podand chains in the model receptor. The pharmacophore and...

  • Identifying the intermediates during the folding/unfolding of protein GB1 with MD simulations. Wu, Xiaomin; Yang, Gang; Zhou, Lijun // Theoretical Chemistry Accounts: Theory, Computation, & Modeling;May2012, Vol. 131 Issue 5, p1 

    Protein folding/unfolding has long represented one of the considerable challenges. In this work, a total of 4.0-μs explicit solvent MD simulations were performed on protein GB1 through the gradual stretching of its end-to-end distance, identifying a wide range of key intermediates and thus...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics