scholarly journals Structural Models for Cytochrome P450�Mediated Catalysis

2003 ◽  
Vol 3 ◽  
pp. 536-545 ◽  
Author(s):  
David F.V. Lewis
Keyword(s):  
Cytochrome P450 ◽  
Homology Modelling ◽  
Structural Models ◽  
Structural Factors ◽  
Subsequent Formation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Current Review ◽  
Mediated Catalysis ◽  
Structure Calculations

This review focuses on the structural models for cytochrome P450 that are improving our knowledge and understanding of the P450 catalytic cycle, and the way in which substrates bind to the enzyme leading to catalytic conversion and subsequent formation of mono-oxygenated metabolites. Various stages in the P450 reaction cycle have now been investigated using X-ray crystallography and electronic structure calculations, whereas homology modelling of mammalian P450s is currently revealing important aspects of pharmaceutical and other xenobiotic metabolism mediated by P450 involvement. These features are explored in the current review on P450-based catalysis, which emphasises the importance of structural modelling to our understanding of this enzyme's function. In addition, the results of various QSAR analyses on series of chemicals, which are metabolised via P450 enzymes, are presented such that the importance of electronic and other structural factors in explaining variations in rates of metabolism can be appreciated.

scholarly journals Modeling of cytochrome P450 (Cyt P450, CYP) channels

2011 ◽  
Vol 25 (2) ◽  
pp. 63-87 ◽  
Author(s):  
Christopher K. Jankowski ◽  
Julien B. Chiasson ◽  
Étienne Dako ◽  
Kathy Doucet ◽  
Marc E. Surette ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Direct Method ◽  
Outer Side ◽  
X Ray ◽  
X Ray Crystallography ◽  
New Methods ◽  
Curved Channels ◽  
Modeling Techniques ◽  
On Line ◽  
Structure Of Proteins

The precise location of a substrate in cytochrome P450 (CYP) governs the orientation of the oxidation position. Such information is generally obtained from biochemical data, but modeling approaches have also been used to explain these locations. We used X-ray data and modeling techniques to distinguish between the series of putative linear or curved channels which lead the substrate from the outer side of the protein to the inner, and then into the heme pocket; these techniques were also used to identify the largest such channels. Two new methods for precisely determining the 3-D structure of proteins using X-ray crystallography were proposed in order to identify these channels: first, the use of both straight and curved channels, and second, the sphere method. These data are compared with Poulos channels, and with Caver (or Mol on line) modeling methodologies. Our methods were developed from studies of the interaction between cytochrome P450CAM(CYP101) fromPseudomonas putida(as expressed inEscherichia coli) and the indolic base β-carboline. Apart from the identification of potential access channels leading to the heme-containing active site, a new explanation was advanced for the substrate's hydroxylation position. The sphere method seems to have potential to become a general and direct method for prediction of substrate access channels from reduced- or low-resolution crystallographic data.

scholarly journals Probing the Structure of [NiFeSe] Hydrogenase with QM/MM Computations

2020 ◽  
Vol 10 (3) ◽  
pp. 781 ◽  
Author(s):  
Samah Moubarak ◽  
N. Elghobashi-Meinhardt ◽  
Daria Tombolelli ◽  
Maria Andrea Mroginski
Keyword(s):  
Iron Oxidation ◽  
Structural Models ◽  
Oxidation States ◽  
Quantum Mechanical ◽  
Desulfovibrio Vulgaris ◽  
X Ray ◽  
X Ray Crystallography ◽  
Desulfovibrio Vulgaris Hildenborough ◽  
Optimized Geometries ◽  
Good Agreement

The geometry and vibrational behavior of selenocysteine [NiFeSe] hydrogenase isolated from Desulfovibrio vulgaris Hildenborough have been investigated using a hybrid quantum mechanical (QM)/ molecular mechanical (MM) approach. Structural models have been built based on the three conformers identified in the recent crystal structure resolved at 1.3 Å from X-ray crystallography. In the models, a diamagnetic Ni2+ atom was modeled in combination with both Fe2+ and Fe3+ to investigate the effect of iron oxidation on geometry and vibrational frequency of the nonproteic ligands, CO and CN-, coordinated to the Fe atom. Overall, the QM/MM optimized geometries are in good agreement with the experimentally resolved geometries. Analysis of computed vibrational frequencies, in comparison with experimental Fourier-transform infrared (FTIR) frequencies, suggests that a mixture of conformers as well as Fe2+ and Fe3+ oxidation states may be responsible for the acquired vibrational spectra.

scholarly journals The Structure of Human Microsomal Cytochrome P450 3A4 Determined by X-ray Crystallography to 2.05-Å Resolution: Fig. 1.

2004 ◽  
Vol 279 (37) ◽  
pp. 38091-38094 ◽  
Author(s):  
Jason K. Yano ◽  
Michael R. Wester ◽  
Guillaume A. Schoch ◽  
Keith J. Griffin ◽  
C. David Stout ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 3A4 ◽  
Microsomal Cytochrome ◽  
X Ray ◽  
X Ray Crystallography ◽  
Microsomal Cytochrome P450

scholarly journals Analysis of Cytochrome P450 CYP119 Ligand-dependent Conformational Dynamics by Two-dimensional NMR and X-ray Crystallography

2015 ◽  
Vol 290 (16) ◽  
pp. 10000-10017 ◽  
Author(s):  
Debashree Basudhar ◽  
Yarrow Madrona ◽  
Sylvie Kandel ◽  
Jed N. Lampe ◽  
Clinton R. Nishida ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Conformational Dynamics ◽  
Two Dimensional ◽  
X Ray ◽  
X Ray Crystallography

scholarly journals Slow thrombin in solution

2005 ◽  
Vol 390 (2) ◽  
Author(s):  
James A. Huntington
Keyword(s):  
Protein Structures ◽  
Structural Models ◽  
Biological Mechanisms ◽  
New Paradigm ◽  
Field Of Study ◽  
X Ray ◽  
X Ray Crystallography ◽  
Exponential Increase ◽  
Biochemical Journal ◽  
Crystallization Conditions

As a tool for understanding biological mechanisms, X-ray crystallography possesses unparalleled power to enlighten, resolve controversy and shift a field of study on to a secure new paradigm. Thanks largely to developments in crystallographic methods, the technique has become accessible to the general biochemist and we have thus witnessed an exponential increase in the number of protein structures deposited every year. It is now commonplace for several structures to be published of the same protein under different crystallization conditions, sometimes resulting in conflicting mechanistic interpretations. Such a controversy has arisen over thrombin's conformational response to Na+ co-ordination, and in this issue of Biochemical Journal, De Filippis and colleagues put the two structural models of thrombin allostery to the test by returning to the techniques of solution biochemistry.

Photosystem II: the engine of life

2003 ◽  
Vol 36 (1) ◽  
pp. 71-89 ◽  
Author(s):  
James Barber
Keyword(s):  
High Resolution ◽  
Photosystem Ii ◽  
Water Oxidation ◽  
Structural Models ◽  
Reaction Centre ◽  
Ps Ii ◽  
X Ray ◽  
X Ray Crystallography ◽  
Redox Active ◽  
Resolution Electron

1. Introduction 712. Electron transfer in PS II 723. (Mn)4cluster and mechanism of water oxidation 734. Organization and structure of the protein subunits 755. Organization of chlorophylls and redox active cofactors 816. Implications arising from the structural models 827. Perspectives 848. Acknowledgements 869. Addendum 8610. References 87Photosystem II (PS II) is a multisubunit membrane protein complex, which uses light energy to oxidize water and reduce plastoquinone. High-resolution electron cryomicroscopy and X-ray crystallography are revealing the structure of this important molecular machine. Both approaches have contributed to our understanding of the organization of the transmembrane helices of higher plant and cyanobacterial PS II and both indicate that PS II normally functions as a dimer. However the high-resolution electron density maps derived from X-ray crystallography currently at 3·7/3·8 Å, have allowed assignments to be made to the redox active cofactors involved in the light-driven water–plastoquinone oxidoreductase activity and to the chlorophyll molecules that absorb and transfer energy to the reaction centre. In particular the X-ray work has identified density that can accommodate the four manganese atoms which catalyse the water-oxidation process. The Mn cluster is located at the lumenal surface of the D1 protein and approximately 7 Å from the redox active tyrosine residue (YZ) which acts an electron/proton transfer link to the primary oxidant P680.+. The lower resolution electron microscopy studies, however, are providing structural models of larger PS II supercomplexes that are ideal frameworks in which to incorporate the X-ray derived structures.

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