The 1.6Å resolution structure of activated D138L mutant of catabolite gene activator protein with two cAMP bound in each monomer

Tao, Wenbing; Gao, Zhonghui; Gao, Zhengya; Zhou, Jiahai; Huang, Zhong‐Xian; Dong, Yuhui; Yu, Shaoning

doi:10.1016/j.ijbiomac.2011.01.009

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…X-ray structures with bound DNA clearly separated from structures not coupled to DNA along this eigenvector, with only two intermediate conformations (which show non-canonical cAMP binding). Remarkably, in spite of the limited time scale of our MD simulations, projections of conformations explored during the MD simulations and experimentally resolved structures [ 9 , 26 – 29 ], on this particular eigenvector showed that the cap2 state is able to follow this motion further than the apo and cap1 states and even overlaps with DNA-bound X-ray structures ( Fig 2B ). This suggests that even though we started from the same active cap2 structure, the sampled conformational space partially diverged during the unbiased MD simulations along directions in agreement with experiments.…”

Section: Resultsmentioning

confidence: 95%

“…Projection of CAP X-ray structures and all simulation data from apo (black), cap1 (blue) and cap2 (orange) states on the first eigenvector obtained from a PCA of available 2 cAMP-bound X-ray structures, either solved in absence of DNA (1–6: 1GN6 [ 9 ], 1HW5 [ 27 ], and 1I6X, 3RDI, 3ROU, 1I5Z –all unpublished) or in presence of DNA (9–11: 1RUO [ 28 ], 1RUN [ 28 ] and 1CGP [ 26 ]). The two intermediate structures (PDB ids: 3QOP (unpublished) and 3KCC [ 29 ]) are not bound to DNA but to two cAMP molecules, localized in between the DBD and β-strand 5, triggering a rotation of the DBD.…”

Section: Resultsmentioning

confidence: 99%

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Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces

et al. 2015

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The Catabolite Activator Protein (CAP) is a showcase example for entropic allostery. For full activation and DNA binding, the homodimeric protein requires the binding of two cyclic AMP (cAMP) molecules in an anti-cooperative manner, the source of which appears to be largely of entropic nature according to previous experimental studies. We here study at atomic detail the allosteric regulation of CAP with Molecular dynamics (MD) simulations. We recover the experimentally observed entropic penalty for the second cAMP binding event with our recently developed force covariance entropy estimator and reveal allosteric communication pathways with Force Distribution Analyses (FDA). Our observations show that CAP binding results in characteristic changes in the interaction pathways connecting the two cAMP allosteric binding sites with each other, as well as with the DNA binding domains. We identified crucial relays in the mostly symmetric allosteric activation network, and suggest point mutants to test this mechanism. Our study suggests inter-residue forces, as opposed to coordinates, as a highly sensitive measure for structural adaptations that, even though minute, can very effectively propagate allosteric signals.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces

et al. 2015

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Neuromodulators as Interdomain Signaling Molecules Capable of Occupying Effector Binding Sites in Bacterial Transcription Factors

Purtov,

Ozoline

2023

IJMS

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Hormones and neurotransmitters are important components of inter-kingdom signaling systems that ensure the coexistence of eukaryotes with their microbial community. Their ability to affect bacterial physiology, metabolism, and gene expression was evidenced by various experimental approaches, but direct penetration into bacteria has only recently been reported. This opened the possibility of considering neuromodulators as potential effectors of bacterial ligand-dependent regulatory proteins. Here, we assessed the validity of this assumption for the neurotransmitters epinephrine, dopamine, and norepinephrine and two hormones (melatonin and serotonin). Using flexible molecular docking for transcription factors with ligand-dependent activity, we assessed the ability of neuromodulators to occupy their effector binding sites. For many transcription factors, including the global regulator of carbohydrate metabolism, CRP, and the key regulator of lactose assimilation, LacI, this ability was predicted based on the analysis of several 3D models. By occupying the ligand binding site, neuromodulators can sterically hinder the interaction of the target proteins with the natural effectors or even replace them. The data obtained suggest that the direct modulation of the activity of at least some bacterial transcriptional factors by neuromodulators is possible. Therefore, the natural hormonal background may be a factor that preadapts bacteria to the habitat through direct perception of host signaling molecules.

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The 1.6Å resolution structure of activated D138L mutant of catabolite gene activator protein with two cAMP bound in each monomer

Cited by 2 publications

References 40 publications

Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces

Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces

Neuromodulators as Interdomain Signaling Molecules Capable of Occupying Effector Binding Sites in Bacterial Transcription Factors

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