Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings

Mitchell, M. R.; Tlusty, Tsvi; Leibler, Stanislas

doi:10.1073/pnas.1609462113

Cited by 76 publications

(108 citation statements)

References 70 publications

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“…Such bulges seem to correlate with EthR's capacity to bind compounds that include 1 to 3 aromatic or aliphatic rings (61). Finite deformations physics theory seems attractive to highlight allosteric regulation pathways by measuring mechanical strain rather than pairwise atomic position deviations (69). Unexpectedly, one of the segments subjected to highest mechanical strain in all TFRs analysed, corresponds to the loop that connects helices α6 and α7 ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisFasR senses long fatty acyl-CoA through a tunnel, inducing DNA-dissociation via a transmission spine

Lara

Diacovich

Trajtenberg

et al. 2020

Preprint

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Mycobacterium tuberculosis is a pathogen with a unique cell envelope including very long fatty acids, implicated in bacterial resistance and host immune modulation. FasR is a two-domain transcriptional activator that belongs to the TetR family of regulators, and plays a central role in mycobacterial longchain fatty acyl-CoA sensing and lipid biosynthesis regulation. We now disclose crystal structures of M. tuberculosis FasR in complex with acyl effector ligands and with DNA, uncovering its sensory and switching mechanisms. A long tunnel traverses the entire effector-binding domain, enabling long fatty acyl effectors to bind. Only when the tunnel is entirely occupied, the protein dimer adopts a rigid configuration, with its DNA-binding domains in an open state that leads to DNA dissociation.Structure-guided point-mutations further support this effector-dependent mechanism. The proteinfolding hydrophobic core, connecting the two domains, is completed by the effector ligand into a continuous spine, explaining the allosteric flexible-to-ordered transition. The transmission spine is conserved in all TetR-like transcription factors, offering new opportunities for anti-tuberculosis drug discovery.2 act as major effector molecules that interact with the host, playing key roles in pathogenicity and also providing a barrier against environmental stress, antibiotics, and the host's immune response (1).Understanding the biogenesis of the mycobacterial cell wall will thus provide with relevant insights into the biology of this pathogen, also identifying potential targets for the development of new antimycobacterial compounds.The outer membrane of Mtb comprises very long-chain fatty acids (mycolic acids), found in the inner leaflet covalently bonded to the arabinogalactan-peptidoglycan layer, and also in the outer leaflet as non-covalently associated lipids in the form of trehalose-mono-and di-mycolate (2). Mycolic acids, a hallmark of Mycobacterium, are synthesized by way of two fatty acid synthase systems, FAS I and FAS II. The multidomain single protein FAS I catalyses de novo biosynthesis of acyl-CoAs in a bimodal fashion rendering C 16-18 and C 24-26 derivatives (3). Long chain acyl-CoAs are used as primers by the FAS II multiprotein system, and iteratively condensed with malonyl-acyl carrier protein (malonyl-ACP) leading to very long-chain meromycolyl-ACPs (up to C 56 ). The latter are eventually condensed to FAS I-synthesized C 24-26 fatty acids (previously activated by the acyl-CoA carboxylase 4 complex (4)) to produce mycolic acids. The long-chain acyl-CoAs generated by FAS I are not only used as precursors of mycolic acids, but also for the biosynthesis of phospholipids, triacylglycerides, diverse polyketides and other complex lipids, relevant for Mtb pathogenicity (5,6). A complex regulatory network integrating all these pathways must exist in order to maintain lipid homeostasis. However, and despite the biological relevance of lipid-derived molecules in Mtb's lifecycle, little is known about the environmental signa...

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisFasR senses long fatty acyl-CoA through a tunnel, inducing DNA-dissociation via a transmission spine

Lara

Diacovich

Trajtenberg

et al. 2020

Preprint

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“…It is to be noted that In our work we have focussed on the projection of the displacements to the non-a ne subspace which is orthogonal to local strain. 46 Since binding hotspots feature large displacements, both strain and strain fluctuations may be large together with large NAP values. NAP however, quantifies the error made in trying to fit the local displacements…”

Section: Discussionmentioning

confidence: 99%

“…The fact that we have a sparsely distributed tail of few relatively very large eigenvalues widely separated from the rest of the spectrum and these large eigenmodes contribute most towards the major conformational changes, clearly demonstrates that our analysis is not a straightforward strain-analysis. 46 Instead, indeed, there is an underlying physics that can be revealed by focusing on the non-a ne subspace P of the total displacement . Non-a nity may play an important role in guiding a majority of the routine functions performed by the proteins.…”

Section: Protein Models and Simulation Detailsmentioning

confidence: 99%

On identifying collective displacements in apo-proteins that reveal eventual binding pathways

Prakashchand

Ahalawat

Khandelia

et al. 2018

Preprint

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Binding of small molecules to proteins often involves large conformational changes in the latter, which open up pathways to the binding site. Observing and pinpointing these rare events in large scale, all-atom, computations of specific protein-ligand complexes, is expensive and to a great extent serendipitous. Further, relevant collective variables which characterise specific binding or un-binding scenarios are still di cult to identify despite the large body of work on the subject. Here, we show that possible primary and secondary binding pathways can be discovered from short simulations of the apo-protein without waiting for an actual binding event to occur. We use a projection formalism, introduced earlier to study deformation in solids, to analyse local atomic displacements into two mutually orthogonal subspaces -those which are "a ne" i.e. expressible as a homogeneous deformation of the native structure, and those which are not. The susceptibility to non-a ne displacements among the various residues in the apo-protein is then shown to correlate with typical binding pathways and sites crucial for allosteric modifications. We validate our observation with all-atom computations of three proteins, T4-Lysozyme, Src kinase and Cytochrome P450.

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“…Recently, Mitchell et al studied crystal structures and NMR spectra of proteins in various regulatory and ligand binding states. 157 They calculated and analyzed distributions of strain throughout several proteins. Strains reveal allosteric and active sites, and suggest that quasi-two-dimensional strained surfaces mediate mechanical couplings between them.…”

Section: Deepened Insights Into Protein Dynamicsmentioning

confidence: 99%

Time-Resolved Resonance Raman Spectroscopy and Application to Studies on Ultrafast Protein Dynamics

Mizutani

2017

Bulletin of the Chemical Society of Japan

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Protein dynamics play a fundamental role in allosteric regulation, which is vital to the function of many proteins. In many proteins, rather than a direct interaction, mutual modulation of properties such as ligand affinity at spatially separated sites is achieved through a conformational change. Conformational changes of proteins are thermally activated processes that involve intramolecular and intermolecular energy exchanges. In this account, I review the work of my team on the development and applications of ultrafast time-resolved resonance Raman spectroscopy to observe functionally important protein dynamics. We gained insights into conformational dynamics upon external stimulus and energy flow with a spatial resolution of a single amino acid residue using time-resolved visible and ultraviolet resonance Raman spectroscopy. The results have contributed to a deeper understanding of the structural nature of protein motion and the relationship of dynamics to function. I discuss the protein dynamics and allosteric mechanism in terms of the nature of the high packing density of protein structures. In addition, I present a view of the future of molecular science on proteins.

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Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings

Cited by 76 publications

References 70 publications

Mycobacterium tuberculosisFasR senses long fatty acyl-CoA through a tunnel, inducing DNA-dissociation via a transmission spine

Mycobacterium tuberculosisFasR senses long fatty acyl-CoA through a tunnel, inducing DNA-dissociation via a transmission spine

On identifying collective displacements in apo-proteins that reveal eventual binding pathways

Time-Resolved Resonance Raman Spectroscopy and Application to Studies on Ultrafast Protein Dynamics

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