Elucidating Allosteric Communications in Proteins with Difference Contact Network Analysis

Yao, Xin‐Qiu; Momin, Mohamed; Hamelberg, Donald

doi:10.1021/acs.jcim.8b00250

Cited by 43 publications

(67 citation statements)

References 57 publications

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“…Contact probability differences were considered significant if their absolute values were greater than the estimated statistical error (0.1) (66) and the two residues were at least three amino acid apart ( i to i + n , n ≥ 3). Residue-residue contacts were further used to identify intrinsic modular structures, or communities, of αβGC cat as previously described (40), which in turn summarized residue wise contact changes by calculating net contact changes between communities. The network analysis and associated graphics generation were performed with bio3d 2.3 (68, 69) and igraph 1.2 (70).…”

Section: Methodsmentioning

confidence: 99%

Synergistic mutations in soluble guanylyl cyclase (sGC) reveal a key role for interfacial regions in the sGC activation mechanism

Childers

Yao

Giannakoulias

et al. 2019

Journal of Biological Chemistry

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Soluble guanylyl cyclase (sGC) is the main receptor for nitric oxide (NO) and a central component of the NO-cGMP pathway, critical to cardiovascular function. NO binding to the N-terminal sensor domain in sGC enhances the cyclase activity of the C-terminal catalytic domain. Our understanding of the structural elements regulating this signaling cascade is limited, hindering structure-based drug design efforts that target sGC to improve the management of cardiovascular diseases. Conformational changes are thought to propagate the NO-binding signal throughout the entire sGC heterodimer, via its coiled-coil domain, to reorient the catalytic domain into an active conformation. To identify the structural elements involved in this signal transduction cascade, here we optimized a cGMP-based luciferase assay that reports on heterologous sGC activity in Escherichia coli and identified several mutations that activate sGC. These mutations resided in the dorsal flaps, dimer interface, and GTP-binding regions of the catalytic domain. Combinations of mutations from these different elements synergized, resulting in even greater activity and indicating a complex cross-talk among these regions. Molecular dynamics simulations further revealed conformational changes underlying the functional impact of these mutations. We propose that the interfacial residues play a central role in the sGC activation mechanism by coupling the coiled-coil domain to the active site via a series of hot spots. Our results provide new mechanistic insights not only into the molecular pathway for sGC activation but also for other members of the larger nucleotidyl cyclase family.

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Section: Methodsmentioning

confidence: 99%

Synergistic mutations in soluble guanylyl cyclase (sGC) reveal a key role for interfacial regions in the sGC activation mechanism

Childers

Yao

Giannakoulias

et al. 2019

Journal of Biological Chemistry

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“…PSNs have been shown to have the potential for bridging graph theory concepts and mechanisms of protein systems. Such connection not only enriches the statistical analysis of networks by providing a class of practical networks with unique properties, but also assists a better (quantitative) understanding of structure–function relationships in proteins [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] .…”

Section: Introductionmentioning

confidence: 96%

Protein conformational switch discerned via network centrality properties

Foutch

Pham

Shen

2021

Computational and Structural Biotechnology Journal

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“…The cutoff itself depends on the kind of structure representation. If connectivity is derived based on atomistic structures, cutoff distances are usually assumed in the range between 4.0 and 5.5 Å 12,24‐31 . In turn, for coarse grained representation R c values between 7 and 8.5 Å are adopted 9‐11,14,32,33 …”

Section: Introductionmentioning

confidence: 99%

Entropy‐based distance cutoff for protein internal contact networks

Sobieraj

Setny

2021

Proteins

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Protein structure networks (PSNs) have long been used to provide a coarse yet meaningful representation of protein structure, dynamics, and internal communication pathways. An important question is what criteria should be applied to construct the network so that to include relevant interresidue contacts while avoiding unnecessary connections. To address this issue, we systematically considered varying residue distance cutoff length and the probability threshold for contact formation to construct PSNs based on atomistic molecular dynamics in order to assess the amount of mutual information within the resulting representations. We found that the minimum in mutual information is universally achieved at the cutoff length of 5 Å, irrespective of the applied contact formation probability threshold in all considered, distinct proteins. Assuming that the optimal PSNs should be characterized by the least amount of redundancy, which corresponds to the minimum in mutual information, this finding suggests an objective criterion for cutoff distance and supports the existing preference towards its customary selection around 5 Å length, typically based to date on heuristic criteria.

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Elucidating Allosteric Communications in Proteins with Difference Contact Network Analysis

Cited by 43 publications

References 57 publications

Synergistic mutations in soluble guanylyl cyclase (sGC) reveal a key role for interfacial regions in the sGC activation mechanism

Synergistic mutations in soluble guanylyl cyclase (sGC) reveal a key role for interfacial regions in the sGC activation mechanism

Protein conformational switch discerned via network centrality properties

Entropy‐based distance cutoff for protein internal contact networks

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