Multivalent weak interactions enhance selectivity of interparticle binding

Scheepers, M. R. W.; IJzendoorn, L.J. van; Prins, Mwj Menno

doi:10.1073/pnas.2003968117

Cited by 35 publications

(39 citation statements)

References 29 publications

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“…There is evidence that multiple weak interactions may be preferred in biological systems to impart greater specificity ( Scheepers et al, 2020 ). Multi-site substrate interactions are a hallmark of mTORC1.…”

Section: Discussionmentioning

confidence: 99%

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace

Heimhalt

Berndt

Wagstaff

et al. 2021

eLife

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The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR’s PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition.

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Section: Discussionmentioning

confidence: 99%

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace

Heimhalt

Berndt

Wagstaff

et al. 2021

eLife

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“…These observations probably suggest that each of the identified compounds could have a high binding affinity to its corresponding antigenic sites Ø or II. Displaying these molecules in a multivalent format (nanoparticle or so) could further enhance their binding affinity [ 62 – 65 ]. Importantly, these small molecules have a better capacity to reach and bind their target without being very immunogenic [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

In silico virtual screening of lead compounds for major antigenic sites in respiratory syncytial virus fusion protein

et al. 2021

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Human respiratory syncytial virus (RSV) is a leading ubiquitous respiratory pathogen in newborn infants, young children, and the elderly, with no vaccine available to date. The viral fusion glycoprotein (RSV F) plays an essential role in the infection process, and it is a primary target of neutralizing antibodies, making it an attractive site for vaccine development. With this in view, there is a persistent need to identify selective antiviral drugs against RSV, targeting the major antigenic sites on the F protein. We aimed to conduct a robust in silico high-throughput drug screening of one million compounds to explore potential inhibitors that bind the major antigenic site Ø and site II on RSV F protein, which are the main target of neutralizing antibodies (NAb). We utilized the three-dimensional crystallographic structure of both antigenic site Ø on pre-F and antigenic II on post-F to screen for potential anti-RSV inhibitors. A library of one million small compounds was docked to explore lead binders in the major antigenic sites by using virtual lab bench CLC Drug Discovery. We also performed Quantitative Structure-Activity and Relationship (QSAR) for the lead best binders known for their antiviral activity. Among one million tested ligands, seven ligands (PubChem ID: 3714418, 24787350, 49828911, 24802036, 79824892, 49726463, and 3139884) were identified as the best binders to neutralizing epitopes site Ø and four ligands (PubChem ID: 865999, 17505357, 24802036, and 24285058) to neutralizing epitopes site II, respectively. These binders exhibited significant interactions with neutralizing epitopes on RSV F, with an average of six H bonds, docking energy of − 15.43 Kcal·mol−1, and minimum interaction energy of − 7.45 Kcal·mol−1. Using in silico virtual screening, we identified potential RSV inhibitors that bind two major antigenic sites on the RSV F protein. Using structure-based design and combination-based drug therapy, identified molecules could be modified to generate the next generation anti-RSV drugs.

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“…(F) Particle targeting. Surfaces of particles can be decorated with ligands which are designed to bond to receptors on the cell surface to immobilize particles at the desired target location (adapted with permission from Scheepers et al, 2020 ).…”

Section: Benefits Of Magnetic Navigation Systems For Scs Lead Placementmentioning

confidence: 99%

“…A critical factor that requires further investigation lies in the permanent attachment of the micro- and nanorobots on the dura mater through chemical modification with targeting ligands ( Figure 2F ), peptides or antibodies to avoid migration from stimulation site (Cheng et al, 2015 ; Tietjen et al, 2018 ; Scheepers et al, 2020 ) and offer regular neurostimulation for the patient. The choice of composite materials must be carefully considered as they need to fulfill all safety criteria for permanently implantable devices (Soto et al, 2020 , 2021 ).…”

Section: Utilizing Untethered Magnetic Micro- and Nanorobots For Scsmentioning

confidence: 99%

Magnetically Guided Catheters, Micro- and Nanorobots for Spinal Cord Stimulation

et al. 2021

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Spinal cord stimulation (SCS) is an established treatment for refractory pain syndromes and has recently been applied to improve locomotion. Several technical challenges are faced by surgeons during SCS lead implantation, particularly in the confined dorsal epidural spaces in patients with spinal degenerative disease, scarring and while targeting challenging structures such as the dorsal root ganglion. Magnetic navigation systems (MNS) represent a novel technology that uses externally placed magnets to precisely steer tethered and untethered devices. This innovation offers several benefits for SCS electrode placement, including enhanced navigation control during tip placement, and the ability to position and reposition the lead in an outpatient setting. Here, we describe the challenges of SCS implant surgery and how MNS can be used to overcome these hurdles. In addition to tethered electrode steering, we discuss the navigation of untethered micro- and nanorobots for wireless and remote neuromodulation. The use of these small-scale devices can potentially change the current standard of practice by omitting the need for electrode and pulse generator implantation or replacement. Open questions include whether small-scale robots can generate an electrical field sufficient to activate neuronal tissue, as well as testing precise navigation, placement, anchoring, and biodegradation of micro- and nanorobots in the in vivo environment.

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Multivalent weak interactions enhance selectivity of interparticle binding

Cited by 35 publications

References 29 publications

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace

In silico virtual screening of lead compounds for major antigenic sites in respiratory syncytial virus fusion protein

Magnetically Guided Catheters, Micro- and Nanorobots for Spinal Cord Stimulation

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