Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/75481
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Type: Journal article
Title: Structural insights into the mechanism of the allosteric transitions of Mycobacterium Tuberculosis cAMP receptor protein
Author: Reddy, M.
Palaninathan, S.
Bruning, J.
Thurman, C.
Smith, D.
Sacchettini, J.
Citation: Journal of Biological Chemistry, 2009; 284(52):36581-36591
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2009
ISSN: 0021-9258
1083-351X
Statement of
Responsibility: 
Manchi C. M. Reddy, Satheesh K. Palaninathan, John B. Bruning, Cory Thurman, Danielle Smith, and James C. Sacchettini
Abstract: The cAMP receptor protein (CRP) from Mycobacterium tuberculosis is a cAMP-responsive global transcriptional regulator, responsible for the regulation of a multitude of diverse proteins. We have determined the crystal structures of the CRP.cAMP and CRP.N(6)-cAMP derivative-bound forms of the enzyme to 2.2- and 2.3 A-resolution, respectively, to investigate cAMP-mediated conformational and structural changes. The allosteric switch from the open, inactive conformation to the closed, active conformation begins with a number of changes in the ligand-binding cavity upon cAMP binding. These subtle structural changes and numerous non-bonding interactions between cAMP, the N-domain residues, and the C-domain helices demonstrate that the N-domain hairpin loop acts as a structural mediator of the allosteric switch. Based on the CRP.N(6)-cAMP crystal structure, binding of N(6)-cAMP with a bulkier methylphenylethyl extension from the N6 atom stabilizes the cAMP-binding domain, N-domain hairpin, and C-terminal domain in a similar manner as that of the CRP.cAMP structure, maintaining structural integrity within the subunits. However, the bulkier N6 extension of N(6)-cAMP (in R conformation) is accommodated only in subunit A with minor changes, whereas in subunit B, the N6 extension is in the S conformation hindering the hinge region of the central helix. As a result, the entire N-domain and the C-domain of subunit B integrated by the cAMP portion of this ligand, together tilt away ( approximately 7 degrees tilt) from central helix C, positioning the helix-turn-helix motif in an unfavorable position for the DNA substrate, asymmetrically. Together, these crystal structures demonstrate the mechanism of action of the cAMP molecule and its role in integrating the active CRP structure.
Keywords: Mycobacterium tuberculosis
Bacterial Proteins
Cyclic AMP
Crystallography, X-Ray
Allosteric Regulation
Protein Structure, Secondary
Protein Structure, Tertiary
Structure-Activity Relationship
Rights: © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M109.041343
Appears in Collections:Aurora harvest 4
Molecular and Biomedical Science publications

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