Advertisement
JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M312516200 on December 15, 2003

J. Biol. Chem., Vol. 279, Issue 10, 9497-9503, March 5, 2004
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
279/10/9497    most recent
M312516200v1
Right arrow Submit a Letter to Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schoch, G. A.
Right arrow Articles by Johnson, E. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schoch, G. A.
Right arrow Articles by Johnson, E. F.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Structure of Human Microsomal Cytochrome P450 2C8

EVIDENCE FOR A PERIPHERAL FATTY ACID BINDING SITE*

Guillaume A. Schoch{ddagger}, Jason K. Yano{ddagger}, Michael R. Wester{ddagger}, Keith J. Griffin{ddagger}, C. David Stout§, and Eric F. Johnson{ddagger}||

From the {ddagger}Department of Molecular and Experimental Medicine and the §Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

A 2.7-Å molecular structure of human microsomal cytochrome P450 2C8 (CYP2C8) was determined by x-ray crystallography. The membrane protein was modified for crystallization by replacement of the hydrophobic N-terminal transmembrane domain with a short hydrophilic sequence before residue 28. The structure of the native sequence is complete from residue 28 to the beginning of a C-terminal histidine tag used for purification. CYP2C8 is one of the principal hepatic drug-metabolizing enzymes that oxidizes therapeutic drugs such as taxol and cerivastatin and endobiotics such as retinoic acid and arachidonic acid. Consistent with the relatively large size of its preferred substrates, the active site volume is twice that observed for the structure of CYP2C5. The extended active site cavity is bounded by the {beta}1 sheet and helix F' that have not previously been implicated in substrate recognition by mammalian P450s. CYP2C8 crystallized as a symmetric dimer formed by the interaction of helices F, F', G', and G. Two molecules of palmitic acid are bound in the dimer interface. The dimer is observed in solution, and mass spectrometry confirmed the association of palmitic acid with the enzyme. This novel finding identifies a peripheral binding site in P450s that may contribute to drug-drug interactions in P450 metabolism.

Received for publication, November 16, 2003 , and in revised form, December 11, 2003.

The atomic coordinates and structure factors (code 1PQ2) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

* This work was supported by National Institutes of Health Grants GM31001 (to E. F. J.) and GM59229 (to C. D. S.). Facilities for computer-assisted sequence analysis, DNA sequencing, and the synthesis of oligonucleotides were supported in part by General Clinical Research Center Grant M01 RR00833 and by the Sam and Rose Stein Charitable Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Dept. of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., MB8, La Jolla, CA 92037. Tel.: 858-784-8738; Fax: 858-784-2857; E-mail: dave{at}scripps.edu.

|| To whom correspondence may be addressed: Dept. of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., MEM-255, La Jolla, CA 92037. Tel.: 858-784-7918; Fax: 858-784-7978; E-mail: johnson{at}scripps.edu.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
N. M. DeVore, B. D. Smith, J. L. Wang, G. H. Lushington, and E. E. Scott
Key Residues Controlling Binding of Diverse Ligands to Human Cytochrome P450 2A Enzymes
Drug Metab. Dispos., June 1, 2009; 37(6): 1319 - 1327.
[Abstract] [Full Text] [PDF]

Home page
 Anticancer ResHome page
K. OHKURA, Y. KAWAGUCHI, Y. WATANABE, Y. MASUBUCHI, Y. SHINOHARA, and H. HORI
Flexible Structure of Cytochrome P450: Promiscuity of Ligand Binding in The CYP3A4 Heme Pocket
Anticancer Res, March 1, 2009; 29(3): 935 - 942.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Li, Z. Chang, Z. Pan, Z.-Q. Fu, and X. Wang
Modes of heme binding and substrate access for cytochrome P450 CYP74A revealed by crystal structures of allene oxide synthase
PNAS, September 16, 2008; 105(37): 13883 - 13888.
[Abstract] [Full Text] [PDF]

Home page
 J BiochemHome page
Y. Wada, M. Mitsuda, Y. Ishihara, M. Watanabe, M. Iwasaki, and S. Asahi
Important Amino Acid Residues that Confer CYP2C19 Selective Activity to CYP2C9
J. Biochem., September 1, 2008; 144(3): 323 - 333.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. A. Schoch, J. K. Yano, S. Sansen, P. M. Dansette, C. D. Stout, and E. F. Johnson
Determinants of Cytochrome P450 2C8 Substrate Binding: STRUCTURES OF COMPLEXES WITH MONTELUKAST, TROGLITAZONE, FELODIPINE, AND 9-CIS-RETINOIC ACID
J. Biol. Chem., June 20, 2008; 283(25): 17227 - 17237.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
R. S. Foti and J. L. Wahlstrom
CYP2C19 Inhibition: The Impact of Substrate Probe Selection on in Vitro Inhibition Profiles
Drug Metab. Dispos., March 1, 2008; 36(3): 523 - 528.
[Abstract] [Full Text] [PDF]

Home page
 Protein Eng Des SelHome page
S. G. Rupasinghe, Z. Wen, T.-L. Chiu, and M. A. Schuler
Helicoverpa zea CYP6B8 and CYP321A1: different molecular solutions to the problem of metabolizing plant toxins and insecticides
Protein Eng. Des. Sel., December 6, 2007; (2007) gzm063v1.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Sansen, J. K. Yano, R. L. Reynald, G. A. Schoch, K. J. Griffin, C. D. Stout, and E. F. Johnson
Adaptations for the Oxidation of Polycyclic Aromatic Hydrocarbons Exhibited by the Structure of Human P450 1A2
J. Biol. Chem., May 11, 2007; 282(19): 14348 - 14355.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
N. Torimoto, I. Ishii, K.-I. Toyama, M. Hata, K. Tanaka, H. Shimomura, H. Nakamura, N. Ariyoshi, S. Ohmori, and M. Kitada
Helices F-G Are Important for the Substrate Specificities of CYP3A7
Drug Metab. Dispos., March 1, 2007; 35(3): 484 - 492.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
Y. Hong, B. Yu, M. Sherman, Y.-C. Yuan, D. Zhou, and S. Chen
Molecular Basis for the Aromatization Reaction and Exemestane-Mediated Irreversible Inhibition of Human Aromatase
Mol. Endocrinol., February 1, 2007; 21(2): 401 - 414.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
C. W. Locuson and T. S. Tracy
Identification of Binding Sites of Non-I-Helix Water Molecules in Mammalian Cytochromes P450
Drug Metab. Dispos., December 1, 2006; 34(12): 1954 - 1957.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
Z. Wen, S. Rupasinghe, G. Niu, M. R. Berenbaum, and M. A. Schuler
CYP6B1 and CYP6B3 of the Black Swallowtail (Papilio polyxenes): Adaptive Evolution through Subfunctionalization
Mol. Biol. Evol., December 1, 2006; 23(12): 2434 - 2443.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
T. Robins, J. Carlsson, M. Sunnerhagen, A. Wedell, and B. Persson
Molecular Model of Human CYP21 Based on Mammalian CYP2C5: Structural Features Correlate with Clinical Severity of Mutations Causing Congenital Adrenal Hyperplasia
Mol. Endocrinol., November 1, 2006; 20(11): 2946 - 2964.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. H. Talasaz, M. Nemat-Gorgani, Y. Liu, P. Stahl, R. W. Dutton, M. Ronaghi, and R. W. Davis
Prediction of protein orientation upon immobilization on biological and nonbiological surfaces
PNAS, October 3, 2006; 103(40): 14773 - 14778.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Ekroos and T. Sjogren
From the Cover: Structural basis for ligand promiscuity in cytochrome P450 3A4
PNAS, September 12, 2006; 103(37): 13682 - 13687.
[Abstract] [Full Text] [PDF]

Home page
 Protein Eng Des SelHome page
J. Baudry, S. Rupasinghe, and M. A. Schuler
Class-dependent sequence alignment strategy improves the structural and functional modeling of P450s
Protein Eng. Des. Sel., August 1, 2006; 19(8): 345 - 353.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
H. Hamamoto, T. Kusudo, N. Urushino, H. Masuno, K. Yamamoto, S. Yamada, M. Kamakura, M. Ohta, K. Inouye, and T. Sakaki
Structure-Function Analysis of Vitamin D 24-Hydroxylase (CYP24A1) by Site-Directed Mutagenesis: Amino Acid Residues Responsible for Species-Based Difference of CYP24A1 between Humans and Rats
Mol. Pharmacol., July 1, 2006; 70(1): 120 - 128.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Rowland, F. E. Blaney, M. G. Smyth, J. J. Jones, V. R. Leydon, A. K. Oxbrow, C. J. Lewis, M. G. Tennant, S. Modi, D. S. Eggleston, et al.
Crystal Structure of Human Cytochrome P450 2D6
J. Biol. Chem., March 17, 2006; 281(11): 7614 - 7622.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Zhao, M. A. White, B. K. Muralidhara, L. Sun, J. R. Halpert, and C. D. Stout
Structure of Microsomal Cytochrome P450 2B4 Complexed with the Antifungal Drug Bifonazole: INSIGHT INTO P450 CONFORMATIONAL PLASTICITY AND MEMBRANE INTERACTION
J. Biol. Chem., March 3, 2006; 281(9): 5973 - 5981.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Kim and D. DellaPenna
Defining the primary route for lutein synthesis in plants: The role of Arabidopsis carotenoid beta-ring hydroxylase CYP97A3
PNAS, February 28, 2006; 103(9): 3474 - 3479.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
B. W. Ogilvie, D. Zhang, W. Li, A. D. Rodrigues, A. E. Gipson, J. Holsapple, P. Toren, and A. Parkinson
GLUCURONIDATION CONVERTS GEMFIBROZIL TO A POTENT, METABOLISM-DEPENDENT INHIBITOR OF CYP2C8: IMPLICATIONS FOR DRUG-DRUG INTERACTIONS
Drug Metab. Dispos., January 1, 2006; 34(1): 191 - 197.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z.-L. Wu, L. M. Podust, and F. P. Guengerich
Expansion of Substrate Specificity of Cytochrome P450 2A6 by Random and Site-directed Mutagenesis
J. Biol. Chem., December 9, 2005; 280(49): 41090 - 41100.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
R. N. Miguel, S. Chen, L. Nikfarjam, S. Kominami, B. Carpenter, C. Dal Pra, C. Betterle, R. Zanchetta, T. Nakamatsu, M. Powell, et al.
Analysis of the interaction between human steroid 21-hydroxylase and various monoclonal antibodies using comparative structural modelling
Eur. J. Endocrinol., December 1, 2005; 153(6): 949 - 961.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
C. J. Kochansky, Y.-Q. Xia, S. Wang, B. Cato, M. Creighton, S. H. Vincent, R. B. Franklin, and J. R. Reed
SPECIES DIFFERENCES IN THE ELIMINATION OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONIST HIGHLIGHTED BY OXIDATIVE METABOLISM OF ITS ACYL GLUCURONIDE
Drug Metab. Dispos., December 1, 2005; 33(12): 1894 - 1904.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
W. Li, H. Liu, E. E. Scott, F. Grater, J. R. Halpert, X. Luo, J. Shen, and H. Jiang
POSSIBLE PATHWAY(S) OF TESTOSTERONE EGRESS FROM THE ACTIVE SITE OF CYTOCHROME P450 2B1: A STEERED MOLECULAR DYNAMICS SIMULATION
Drug Metab. Dispos., July 1, 2005; 33(7): 910 - 919.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
F. G. Riepe, S. Tatzel, W. G. Sippell, J. Pleiss, and N. Krone
Congenital Adrenal Hyperplasia: The Molecular Basis of 21-Hydroxylase Deficiency in H-2aw18 Mice
Endocrinology, June 1, 2005; 146(6): 2563 - 2574.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
H. Hichiya, T. Tanaka-Kagawa, A. Soyama, H. Jinno, S. Koyano, N. Katori, E. Matsushima, S. Uchiyama, H. Tokunaga, H. Kimura, et al.
FUNCTIONAL CHARACTERIZATION OF FIVE NOVEL CYP2C8 VARIANTS, G171S, R186X, R186G, K247R, AND K383N, FOUND IN A JAPANESE POPULATION
Drug Metab. Dispos., May 1, 2005; 33(5): 630 - 636.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
T. Robins, M. Barbaro, S. Lajic, and A. Wedell
Not All Amino Acid Substitutions of the Common Cluster E6 Mutation in CYP21 Cause Congenital Adrenal Hyperplasia
J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2148 - 2153.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C.-H. Yun, K.-H. Kim, M. W. Calcutt, and F. P. Guengerich
Kinetic Analysis of Oxidation of Coumarins by Human Cytochrome P450 2A6
J. Biol. Chem., April 1, 2005; 280(13): 12279 - 12291.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
M. Delaforge, A. Pruvost, L. Perrin, and F. Andre
CYTOCHROME P450-MEDIATED OXIDATION OF GLUCURONIDE DERIVATIVES: EXAMPLE OF ESTRADIOL-17{beta}-GLUCURONIDE OXIDATION TO 2-HYDROXY-ESTRADIOL-17{beta}-GLUCURONIDE BY CYP 2C8
Drug Metab. Dispos., March 1, 2005; 33(3): 466 - 473.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
R. L. Walsky, R. S. Obach, E. A. Gaman, J.-P. R. Gleeson, and W. R. Proctor
SELECTIVE INHIBITION OF HUMAN CYTOCHROME P4502C8 BY MONTELUKAST
Drug Metab. Dispos., March 1, 2005; 33(3): 413 - 418.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
R. L. Walsky, E. A. Gaman, and R. S. Obach
Examination of 209 Drugs for Inhibition of Cytochrome P450 2C8
J. Clin. Pharmacol., January 1, 2005; 45(1): 68 - 78.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
D. A. Murtazina, U. Andersson, I.-S. Hahn, I. Bjorkhem, G. A. S. Ansari, and I. A. Pikuleva
Phospholipids modify substrate binding and enzyme activity of human cytochrome P450 27A1
J. Lipid Res., December 1, 2004; 45(12): 2345 - 2353.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. K. Yano, M. R. Wester, G. A. Schoch, K. J. Griffin, C. D. Stout, and E. F. Johnson
The Structure of Human Microsomal Cytochrome P450 3A4 Determined by X-ray Crystallography to 2.05-A Resolution
J. Biol. Chem., September 10, 2004; 279(37): 38091 - 38094.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. R. Wester, J. K. Yano, G. A. Schoch, C. Yang, K. J. Griffin, C. D. Stout, and E. F. Johnson
The Structure of Human Cytochrome P450 2C9 Complexed with Flurbiprofen at 2.0-A Resolution
J. Biol. Chem., August 20, 2004; 279(34): 35630 - 35637.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. E. Scott, M. A. White, Y. A. He, E. F. Johnson, C. D. Stout, and J. R. Halpert
Structure of Mammalian Cytochrome P450 2B4 Complexed with 4-(4-Chlorophenyl)imidazole at 1.9-A Resolution: INSIGHT INTO THE RANGE OF P450 CONFORMATIONS AND THE COORDINATION OF REDOX PARTNER BINDING
J. Biol. Chem., June 25, 2004; 279(26): 27294 - 27301.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
Advertisement
spacer
Advertisement
Advertisement