scholarly journals Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites

2017 ◽  
Vol 4 (3) ◽  
pp. 032104 ◽  
Author(s):  
Nicholas M. Pearce ◽  
Anthony R. Bradley ◽  
Tobias Krojer ◽  
Brian D. Marsden ◽  
Charlotte M. Deane ◽  
...  
Keyword(s):  
Binding Sites ◽  
Analysis Method ◽  
Density Analysis ◽  
Cryptic Binding Sites

scholarly journals Investigating Cryptic Binding Sites by Molecular Dynamics Simulations

2020 ◽  
Vol 53 (3) ◽  
pp. 654-661 ◽  
Author(s):  
Antonija Kuzmanic ◽  
Gregory R. Bowman ◽  
Jordi Juarez-Jimenez ◽  
Julien Michel ◽  
Francesco L. Gervasio
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Sites ◽  
Cryptic Binding Sites ◽  
Dynamics Simulations

scholarly journals Cryptic binding sites on proteins: definition, detection, and druggability

2018 ◽  
Vol 44 ◽  
pp. 1-8 ◽  
Author(s):  
Sandor Vajda ◽  
Dmitri Beglov ◽  
Amanda E Wakefield ◽  
Megan Egbert ◽  
Adrian Whitty
Keyword(s):  
Binding Sites ◽  
Cryptic Binding Sites

scholarly journals A Study on Economic Spatial Structure of Urban Agglomerations in Guangdong-Hong Kong-Macao Greater Bay Area

2018 ◽  
Vol 13 (10) ◽  
pp. 63
Author(s):  
Jincheng Yang ◽  
Xinqu Xia ◽  
Mu Zhang
Keyword(s):  
Hong Kong ◽  
Centrality Measures ◽  
Analysis Method ◽  
Topsis Method ◽  
Urban Agglomerations ◽  
Urban Economic ◽  
The Core ◽  
Bay Area ◽  
Network Connection ◽  
Density Analysis

Based on the multi-index data of 11 cities in Guangdong-Hong Kong-Macao Greater Bay in 2016, the urban economic quality was calculated by TOPSIS method. Applying the modified gravitational model, the economy spatial linkage characteristics of core city-to-periphery city and periphery city-to-periphery city were analyzed. In addition, based on the method of network density analysis, centrality measures, core-periphery structure analysis to make a further verification about facts carried out from spatial connection analysis. This study shows that the Guangdong-Hong Kong-Macao Bay has an obvious core-periphery structure, and the overall economic network connection of Greater Bay is not strong. Guangdong-Shenzhen-Hong Kong is the core urban agglomeration in the Greater Bay Area. Dongguan and Foshan are transforming from marginal cities to semi-marginal cities. The marginal cities are limited by geographical distance or the economic environment, which leads to their development far behind the overall development of the Greater Bay Area. Finally, combined with the new wooden barrel theory and location advantage analysis method, advices were carried out to build a higher-level of the Greater Bay Area in future by dividing the Greater Bay Area into three major urban agglomerations. Urban agglomerations were proposed to meet the resources and industrial demands of the core urban imperfections and drive the economic development of the marginal cities at the same time.

Focal Adhesion Mechanotransduction Regulates Stiffness-Directed Differentiation

2013 ◽  
Author(s):  
Andrew W. Holle ◽  
Juan Carlos Del Alamo ◽  
Adam J. Engler
Keyword(s):  
Binding Sites ◽  
Human Mesenchymal Stem Cells ◽  
Stem Cell Differentiation ◽  
Strain Gauges ◽  
Directed Differentiation ◽  
Force Transmission ◽  
Specific Proteins ◽  
Cryptic Binding Sites ◽  
Myogenic Markers

Human mesenchymal stem cells (hMSCs) are capable of differentiating into mesodermal lineages, with their fate mirroring the tissue lineage possessing a matching in vivo stiffness. The precise mechanisms responsible for this mechanotransduction-induced change in fate are unknown beyond the requirement for force transmission from the extracellular niche through to the nucleus. As a result of cellular contraction, linker proteins connecting the cytoskeleton to the extracellular matrix (ECM) are exposed to differing levels of force and deform to different extents based on the adjacent ECM’s stiffness. Therefore, some of these linker proteins could act as ‘molecular strain gauges,’ as they have been shown to unfold in response to this force. The unfolding process could result in exposure of cryptic binding sites and induction of new signaling pathways. For example, talin exposes multiple vinculin binding sites under physiological force [1]. Vinculin binds at either end to talin and actin and is thought to change its conformation in conjunction with this force [2] similar to how a strain gauge works. Here we show that force-dependent changes in vinculin recruit MAPK1, inducing a signaling cascade that results in the expression of myogenic markers. Together these data suggest that specific proteins may act as ‘molecular strain gauges’ and play a role in mechanosensitive stem cell differentiation.

scholarly journals Role of the Transcription Activator Ste12p as a Repressor of PRY3 Expression

2006 ◽  
Vol 26 (21) ◽  
pp. 7901-7912 ◽  
Author(s):  
Kellie S. Bickel ◽  
David R. Morris
Keyword(s):  
Binding Sites ◽  
Full Length ◽  
Transcription Activator ◽  
Pheromone Response ◽  
Reading Frame ◽  
Short Transcript ◽  
Cryptic Binding Sites ◽  
Full Length Transcript ◽  
Transcript Evidence

ABSTRACT Mating pheromone represses synthesis of full-length PRY3 mRNA, and a new transcript appears simultaneously with its 5′ terminus 452 nucleotides inside the open reading frame (ORF). Synthesis of this shorter transcript results from activation of a promoter within the PRY3 locus, and its production is concomitant with the rapid disappearance of the full-length transcript. Evidence is consistent with the pheromone-induced transcription factor Ste12p binding two pheromone response elements within the PRY3 promoter, directly impeding transcription of the full-length mRNA while simultaneously inducing initiation of the short transcript. This process depends on a TATA box within the PRY3 ORF. Expression of full-length PRY3 inhibited mating, while no disadvantage was detectable for cells unable to make the short transcript. Therefore, Ste12p is utilized as a repressor of full-length PRY3 transcription, ensuring efficient mating. There is no evidence that production of the short PRY3 transcript is anything more than an adventitious by-product of this mechanism. It is possible that cryptic binding sites for transcriptional activators may occur frequently within genomes and have the potential of evolving for rapid, gene-specific repression by mechanisms analogous to PRY3. PRY3 regulation provides a model for the coordination of both inductive and repressive activities within a regulatory network.

scholarly journals Weak catch bonds make strong networks

2020 ◽  
Author(s):  
Yuval Mulla ◽  
Mario J Avellaneda ◽  
Antoine Roland ◽  
Lucia Baldauf ◽  
Sander J Tans ◽  
...  
Keyword(s):  
Binding Sites ◽  
Fluid Flows ◽  
Actin Networks ◽  
On Demand ◽  
High Tension ◽  
Weak Binding ◽  
Cryptic Binding Sites ◽  
Current Paradigm ◽  
Catch Bonds

Molecular catch bonds are ubiquitous in biology and well-studied in the context of leukocyte extravasion1, cellular mechanosensing2,3, and urinary tract infection4. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this remarkable ability enables cells to increase their adhesion in fast fluid flows1,4, and hence provides ‘strength-on-demand’. Recently, cytoskeletal crosslinkers have been discovered that also display catch bonding5–8. It has been suggested that they strengthen cells, following the strength-on-demand paradigm9,10. However, catch bonds tend to be weaker compared to regular (slip) bonds because they have cryptic binding sites that are often inactive11–13. Therefore, the role of catch bonding in the cytoskeleton remains unclear. Here we reconstitute cytoskeletal actin networks to show that catch bonds render them both stronger and more deformable than slip bonds, even though the bonds themselves are weaker. We develop a model to show that weak binding allows the catch bonds to mitigate crack initiation by moving from low- to high-tension areas in response to mechanical loading. By contrast, slip bonds remain trapped in stress-free areas. We therefore propose that the mechanism of catch bonding is typified by dissociation-on-demand rather than strength-on-demand. Dissociation-on-demand can explain how both cytolinkers5–8,10,14,15 and adhesins1,2,4,12,16–20 exploit continuous redistribution to combine mechanical strength with the adaptability required for movement and proliferation21. Our findings provide a mechanistic understanding of diseases where catch bonding is compromised11,12 such as kidney focal segmental glomerulosclerosis22,23, caused by the α-actinin-4 mutant studied here. Moreover, catch bonds provide a route towards creating life-like materials that combine strength with deformability24.

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