NDLI: Defining CYP3A4 structural responses to substrate binding. Raman spectroscopic studies of a nanodisc-incorporated mammalian Cytochrome P450

Content Provider	PubMed Central
Author	Mak, Piotr J. Denisov, Ilia G. Grinkova, Yelena V. Sligar, Stephen G. Kincaid, James R.
Abstract	Resonance Raman (RR) spectroscopy is used to help define active site structural responses of nanodisc-incorporated CYP3A4 to the binding of three substrates; bromocriptine (BC), erythromycin (ERY) and testosterone (TST). We demonstrate that nanodisc-incorporated assemblies reveal much more well-defined active site RR spectroscopic responses compared to those normally obtained with the conventional, detergent-stabilized, sampling strategies. While, ERY and BC are known to bind to CYP3A4 with a 1:1 stoichiometry, only the BC induces a substantial conversion from low- to high-spin state, as clearly manifested in the RR spectra acquired herein. The third substrate, TST, displays significant homotropic interactions within CYP3A4, the active site binding up to 3 molecules of this substrate, with the functional properties varying in response to binding of individual substrate molecules. While such behavior seemingly suggests the possibility that each substrate binding event induces functionally important heme structural changes, up to this time spectroscopic evidence for such structural changes has not been available. The current RR spectroscopic studies show clearly that accommodation of different size substrates, and different loading of TST, do not significantly affect the structure of the substrate-bound ferric heme. However, it is here demonstrated that the nature and number of bound substrates do have an extraordinary influence on the conformation of bound exogenous ligands, such as CO or dioxygen and its reduced forms, implying an effective mechanism whereby substrate structure can impact reactivity of intermediates so as to influence function, as reflected in the diverse reactivity of this drug metabolizing cytochrome.
Related Links	http://dx.doi.org/10.1021/ja105869p
Ending Page	1366
Page Count	10
Starting Page	1357
File Format	PDF
ISSN	00027863
e-ISSN	15205126
Journal	Journal of the American Chemical Society
Issue Number	5
Volume Number	133
Language	English
Publisher Date	2011-02-09
Access Restriction	Open
Subject Keyword	Colloid and Surface Chemistry Biochemistry Chemistry(all) Catalysis Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Chemistry Colloid and Surface Chemistry Biochemistry Catalysis

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Defining the Structural Consequences of Mechanism-Based Inactivation of Mammalian Cytochrome P450 2B4 Using Resonance Raman Spectroscopy

Structural and Thermodynamic Basis of (+)-α-Pinene Binding to Human Cytochrome P450 2B6

Defining Resonance Raman Spectral Responses to Substrate Binding by Cytochrome P450 from Pseudomonas putida

Redox Potential Control by Drug Binding to Cytochrome P450 3A4

Preparation, Characterization, and Substrate Metabolism of Gold-Immobilized Cytochrome P450 2C9

Resonance Raman Detection of the Hydroperoxo Intermediate in the Cytochrome P450 Enzymatic Cycle

Cytochrome P450 Compound I

StructuralAdaptability Facilitates Histidine HemeLigation in a Cytochrome P450

Allosteric Effects on Substrate Dissociation from Cytochrome P450 3A4 in Nanodiscs Observed by Ensemble and Single-Molecule Fluorescence Spectroscopy

Defining CYP3A4 structural responses to substrate binding. Raman spectroscopic studies of a nanodisc-incorporated mammalian Cytochrome P450

Similar Documents

Defining the Structural Consequences of Mechanism-Based Inactivation of Mammalian Cytochrome P450 2B4 Using Resonance Raman Spectroscopy

Structural and Thermodynamic Basis of (+)-α-Pinene Binding to Human Cytochrome P450 2B6

Defining Resonance Raman Spectral Responses to Substrate Binding by Cytochrome P450 from Pseudomonas putida

Redox Potential Control by Drug Binding to Cytochrome P450 3A4

Preparation, Characterization, and Substrate Metabolism of Gold-Immobilized Cytochrome P450 2C9

Resonance Raman Detection of the Hydroperoxo Intermediate in the Cytochrome P450 Enzymatic Cycle

Cytochrome P450 Compound I

StructuralAdaptability Facilitates Histidine HemeLigation in a Cytochrome P450

Allosteric Effects on Substrate Dissociation from Cytochrome P450 3A4 in Nanodiscs Observed by Ensemble and Single-Molecule Fluorescence Spectroscopy

Defining CYP3A4 structural responses to substrate binding. Raman spectroscopic studies of a nanodisc-incorporated mammalian Cytochrome P450