Methotrexate, a small molecular scaffold targeting Kv1.3 channel extracellular pore region

We report a curious porous molecular crystal that is devoid of the common traits of related systems. Namely, the molecule does not rely on directional hydrogen bonds to enforce open packing; and it offers neither large concave faces (i.e., high internal free volume) to frustrate close packing, nor any inherently built-in cavity like in the class of organic cages. Instead, the permanent porosity (as unveiled by the X-ray crystal structure and CO<sub>2</sub> sorption studies) arises from the strong push-pull units built into a Sierpinski-like molecule that features four symmetrically backfolded (<b>SBF</b>) side arms. Each side arm consists of the 1,1,4,4-tetracyanobuta-1,3-diene acceptor (TCBD) coupled with the dimethylaminophenyl donor, which is conveniently installed by a cycloaddition-retroelectrocyclization (CA-RE) reaction. Unlike the poor/fragile crystalline order of many porous molecular solids, the molecule here readily crystallizes and the crystalline phase can be easily deposited into thin films from solutions. Moreover, both the bulk sample and thin film exhibit excellent thermal stability with the porous crystalline order maintained even at 200 °C. The intermolecular forces underlying this robust porous molecular crystal likely include the strong dipole interactions and the multiple C···N and C···O short contacts afforded by the strongly donating and accepting groups integrated within the rigid molecular scaffold.

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Faculty Opinions recommendation of Assembling OX40 aptamers on a molecular scaffold to create a receptor-activating aptamer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1121768.578840 ◽

2008 ◽

Author(s):

Andrew Ellington

Keyword(s):

Molecular Scaffold

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Missense Mutation in the Pore Region of HERG Causes Familial Long QT Syndrome

Circulation ◽

10.1161/01.cir.93.10.1791 ◽

1996 ◽

Vol 93 (10) ◽

pp. 1791-1795 ◽

Cited By ~ 53

Author(s):

D. Woodrow Benson ◽

Calum A. MacRae ◽

Mark R. Vesely ◽

Edward P. Walsh ◽

J.G. Seidman ◽

...

Keyword(s):

Missense Mutation ◽

Long Qt Syndrome ◽

Long Qt ◽

Pore Region ◽

Qt Syndrome

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Kv1.3 channel, a targetable piece in the complex jigsaw puzzle of vascular calcification?

Function ◽

10.1093/function/zqaa049 ◽

2020 ◽

Author(s):

Maria F Gomez

Keyword(s):

Vascular Calcification ◽

Jigsaw Puzzle ◽

Kv1.3 Channel

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The paracaspase MALT1 in psoriasis

Biological Chemistry ◽

10.1515/hsz-2021-0250 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Stephan Hailfinger ◽

Klaus Schulze-Osthoff

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Transcription Factors ◽

Skin Disease ◽

Cell Types ◽

Cytokine Receptors ◽

Molecular Scaffold ◽

Therapeutic Implications ◽

Stimulation Of

Abstract Psoriasis is a frequent autoimmune-related skin disease, which involves various cell types such as T cells, keratinocytes and dendritic cells. Genetic variations, such as mutations of CARD14, can promote the development of the disease. CARD14 mutations as well as the stimulation of immune and cytokine receptors activate the paracaspase MALT1, a potent activator of the transcription factors NF-κB and AP-1. The disease-promoting role of MALT1 for psoriasis is mediated by both its protease activity as well as its molecular scaffold function. Here, we review the importance of MALT1-mediated signaling and its therapeutic implications in psoriasis.

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Characterization of microbial antifreeze protein with intermediate activity suggests that a bound-water network is essential for hyperactivity

Scientific Reports ◽

10.1038/s41598-021-85559-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

N. M.-Mofiz Uddin Khan ◽

Tatsuya Arai ◽

Sakae Tsuda ◽

Hidemasa Kondo

Keyword(s):

Crystal Structure ◽

Basal Plane ◽

Molecular Mechanisms ◽

Bound Water ◽

Hydrophobic Hydration ◽

Water Network ◽

Molecular Scaffold ◽

Intermediate Activity ◽

Mold Fungus ◽

Antifreeze Activity

AbstractAntifreeze proteins (AFPs) inhibit ice growth by adsorbing onto specific ice planes. Microbial AFPs show diverse antifreeze activity and ice plane specificity, while sharing a common molecular scaffold. To probe the molecular mechanisms responsible for AFP activity, we here characterized the antifreeze activity and crystal structure of TisAFP7 from the snow mold fungus Typhula ishikariensis. TisAFP7 exhibited intermediate activity, with the ability to bind the basal plane, compared with a hyperactive isoform TisAFP8 and a moderately active isoform TisAFP6. Analysis of the TisAFP7 crystal structure revealed a bound-water network arranged in a zigzag pattern on the surface of the protein’s ice-binding site (IBS). While the three AFP isoforms shared the water network pattern, the network on TisAFP7 IBS was not extensive, which was likely related to its intermediate activity. Analysis of the TisAFP7 crystal structure also revealed the presence of additional water molecules that form a ring-like network surrounding the hydrophobic side chain of a crucial IBS phenylalanine, which might be responsible for the increased adsorption of AFP molecule onto the basal plane. Based on these observations, we propose that the extended water network and hydrophobic hydration at IBS together determine the TisAFP activity.

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