4r8h

The role of protein-ligand contacts in allosteric regulation of the Escherichia coli Catabolite Activator Protein

spinqualitylabelsall models 4r8h, resolution 1.46Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4r8h is a 2 chain structure with sequence from Ecoli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, SP1 Gene: crp, cap, csm, b3357, JW5702 (ECOLI) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CRP_ECOLI] This protein complexes with cyclic AMP and binds to specific DNA sites near the promoter to regulate the transcription of several catabolite-sensitive operons. The protein induces a severe bend in the DNA. Acts as a negative regulator of its own synthesis as well as for adenylate cyclase (cyaA), which generates cAMP. Publication Abstract from PubMed Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distant site. Both experimental and theoretical evidence demonstrate that allostery can be communicated through altered slow relaxation protein dynamics without conformational change. The Catabolite Activator Protein (CAP) of Escherichia coli is an exemplar for the analysis of such entropically driven allostery. Negative allostery in CAP occurs between identical cAMP binding sites. Changes to the cAMP-binding pocket can therefore impact the allosteric properties of CAP. Here we demonstrate, through a combination of coarse-grained modelling, isothermal calorimetry, and structural analysis, that decreasing the affinity of CAP for cAMP enhances negative cooperativity through an entropic penalty for ligand binding. The use of variant cAMP ligands indicates the data is not explained by structural heterogeneity between protein mutants. We observe computationally that altered interaction strength between CAP and cAMP variously modifies the change in allosteric cooperativity due to second-site CAP mutations. As the degree of correlated motion between the cAMP contacting site and a second site on CAP increases, there is a tendency for computed double mutations at these sites to drive CAP towards non-cooperativity. Naturally occurring pairs of covarying residues in CAP do not display this tendency, suggesting a selection pressure to fine tune allostery on changes to the CAP ligand-binding pocket without a drive to a non-cooperative state. In general, we hypothesize an evolutionary selection pressure to retain slow relaxation dynamics-induced allostery in proteins in which evolution of the ligand-binding site is occurring. The Role of Protein-Ligand Contacts in Allosteric Regulation of the Escherichia coli Catabolite Activator Protein.,Townsend PD, Rodgers TL, Glover LC, Korhonen HJ, Richards SA, Colwell LJ, Pohl E, Wilson MR, Hodgson DR, McLeish TC, Cann MJ J Biol Chem. 2015 Jul 16. pii: jbc.M115.669267. PMID:26187469 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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