Biomolecular Modelling & Design Division

Allostery in Its Many Disguises: From Theory to Applications

Published date : 01 Apr 2019

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood.

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Journal Paper
journal
Structure 27, 2019 Jan 17. pii: S0969-2126(19)30003-6. doi: 10.1016/j.str.2019.01.003
Impact Factor
4.907

Structure mapping of dengue and Zika viruses reveals functional long-range interactions

Published date : 29 Mar 2019

Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform structure and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates.

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Journal Paper
journal
Nature Communications, 2019 Mar 29;10(1):1408. doi: 10.1038/s41467-019-09391-8
Impact Factor
12.353

"Inhibiting S100B(ββ) for Activating Wild-Type p53: Design of Stapled Peptides"

Published date : 14 Mar 2019

S100B(ββ) is a member of the S100B protein family and is distributed in a cell-specific manner. Its levels are elevated in several cancers such as malignant melanoma and correlate directly with poor prognosis in patients. S100B(ββ) directly interacts with the tumor suppressor p53, inhibiting tetramerization and protein kinase C-dependent phosphorylation, consequently decreasing p53 DNA binding and transcriptional activity, and preventing apoptosis. Thus, S100B(ββ) is being pursued as a target for therapeutic inhibition.

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Journal Paper
journal
ACS Omega 2019, 5, Pg 5335-5344, doi: 10.1021/acsomega.9b00097

An inter-subunit protein-peptide interface that stabilizes the specific activity and oligomerization of the AAA+ chaperone Reptin

Published date : 09 Mar 2019

Reptin is a member of the AAA+ superfamily whose members can exist in equilibrium between monomeric apo forms and ligand bound hexamers. Inter-subunit protein-protein interfaces that stabilize Reptin in its oligomeric state are not well-defined. A self-peptide binding assay identified a protein-peptide interface mapping to an inter-subunit “rim” of the hexamer bridged by Tyrosine-340. A Y340A mutation reduced ADP-dependent oligomer formation using a gel filtration assay, suggesting that Y340 forms a dominant oligomer stabilizing side chain.

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Journal Paper
journal
Journal of Proteomics, Vol. 199, 2019, Pg 89-101 doi:10.1016/j.jprot.2019.02.012
Impact Factor
3.722

Insights into water accessible pathways and the inactivation mechanism of proton translocation by the membrane-embedded domain of V-type ATPases

Published date : 01 Mar 2019

V-type ATPases are multi-protein complexes, which acidify cellular compartments in eukaryotes. They pump protons against an ion gradient, driven by a mechano-chemical framework that exploits ATP hydrolysis as an energy source. This process drives the rotation of the so-called c-ring, a membrane embedded complex in the Vo-domain of the V-type ATPase, resulting in translocation of protons across the membrane. One way in which the enzyme is regulated is by disassembly and reassembly of the V1-domain with the Vo-domain, which inactivates and reactivates the enzyme, respectively.

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Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1861, Issue 5, 1 May 2019, Pg 1004-1010, doi: 10.1016/j.bbamem.2019.02.010
Impact Factor
3.438

The disordered plant dehydrin Lti30 protects the membrane during water-related stress by cross-linking lipids

Published date : 28 Feb 2019

Dehydrins are intrinsically disordered proteins, generally expressed in plants as a response to embryogenesis and water-related stress. Their suggested functions are in membrane stabilization and cell protection. All dehydrins contain at least one copy of the highly conserved K-segment, proposed to be a membrane binding motif. The dehydrin Lti30 (Arabidopsis thaliana) is upregulated during cold and drought stress conditions and comprises six K-segments, each with two adjacent histidines. Lti30 interacts with the membrane electrostatically via pH dependent protonation of the histidines.

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Journal Paper
journal
Journal of Biological Chemistry, 28 Feb 2019, doi: 10.1074/jbc.RA118.007163
Impact Factor
4.011

Toward Comprehensive Allosteric Control over Protein Activity

Published date : 28 Feb 2019

Universality of allosteric signaling in proteins, molecular machines, and receptors complemented by the great advantages of prospected allosteric drugs in the highly specific, non-competitive, and modulatory nature of their actions calls for deeper theoretical understanding of allosteric communication. We present a computational model that makes it possible to tackle the problem of modulating the energetics of protein allosteric communication.

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Journal Paper
journal
Structure 27, Pg 1-13, May 7, 2019, doi: 10.1016/j.str.2019.01.1016
Impact Factor
4.907

Discovering Putative Protein Targets of Small Molecules: A Study of the p53 Activator Nutlin

Published date : 22 Feb 2019

Small molecule drugs bind to a pocket in disease causing target proteins based on complementarity in shape and physicochemical properties. There is a likelihood that other proteins could have binding sites that are structurally similar to the target protein. Binding to these other proteins could alter their activities leading to off target effects of the drug. One such small molecule drug Nutlin binds the protein MDM2, which is upregulated in several types of cancer and is a negative regulator of the tumor suppressor protein p53.

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Journal Paper
journal
Journal of Chemical Information and Modeling, 2019. 59, (4) Pg. 1529-1546, doi: 10.1021/acs.jcim.8b00762
Impact Factor
3.804

Kinetic and thermodynamic effects of phosphorylation on p53 binding to MDM2

Published date : 24 Jan 2019

p53 is frequently mutated in human cancers. Its levels are tightly regulated by the E3 ubiquitin ligase MDM2. The complex between MDM2 and p53 is largely formed by the interaction between the N-terminal domain of MDM2 and the N-terminal transactivation (TA) domain of p53 (residues 15-29). We investigated the kinetic and thermodynamic basis of the MDM2/p53 interaction by using wild-type and mutant variants of the TA domain. We focus on the effects of phosphorylation at positions Thr18 and Ser20 including their substitution with phosphomimetics.

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Journal Paper
journal
Scientific Reports 9, Article no: 693 (2019). doi: 10.1038/s41598-018-36589-5
Impact Factor
4.122

Infectivity of Dengue Virus Serotypes 1 and 2 Is Correlated with E-Protein Intrinsic Dynamics but Not to Envelope Conformations

Published date : 24 Jan 2019

Dengue is a mosquito-borne virus with dire health and economic impacts. Dengue is responsible for an estimated 390 million infections per year, with dengue 2 (DENV2) being the most virulent strain among the four serotypes. Interestingly, it is also in strains of this serotype that temperature-dependent large-scale morphological changes, termed “breathing,” have been observed. Although the structure of these morphologies has been solved to 3.5-Å resolution, the dynamics of the viral envelope are unknown.

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Journal Paper
journal
Structure, 27, Pg 1-13, 2019, doi: 10.1016/j.str.2018.12.006
Impact Factor
4.907