Binding of the vasodilator peptides adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) to the class B G protein-coupled receptor calcitonin receptor-like receptor (CLR) is modulated by ...receptor activity-modifying proteins (RAMPs). RAMP1 favors CGRP, whereas RAMP2 and RAMP3 favor AM. Crystal structures of peptide-bound RAMP1/2-CLR extracellular domain (ECD) heterodimers suggested RAMPs alter ligand preference through direct peptide contacts and allosteric modulation of CLR. Here, we probed this dual mechanism through rational structure-guided design of AM and CGRP antagonist variants. Variants were characterized for binding to purified RAMP1/2-CLR ECD and for antagonism of the full-length CGRP (RAMP1:CLR), AM
(RAMP2:CLR), and AM
(RAMP3:CLR) receptors. Short nanomolar affinity AM(37-52) and CGRP(27-37) variants were obtained through substitutions including AM S45W/Q50W and CGRP K35W/A36S designed to stabilize their
-turn. K46L and Y52F substitutions designed to exploit RAMP allosteric effects and direct peptide contacts, respectively, yielded AM variants with selectivity for the CGRP receptor over the AM
receptor. AM(37-52) S45W/K46L/Q50W/Y52F exhibited nanomolar potency at the CGRP receptor and micromolar potency at AM
A 2.8-Å resolution crystal structure of this variant bound to the RAMP1-CLR ECD confirmed that it bound as designed. CGRP(27-37) N31D/S34P/K35W/A36S exhibited potency and selectivity comparable to the traditional antagonist CGRP(8-37). Giving this variant the ability to contact RAMP2 through the F37Y substitution increased affinity for AM
, but it still preferred the CGRP receptor. These potent peptide antagonists with altered selectivity inform the development of AM/CGRP-based pharmacological tools and support the hypothesis that RAMPs alter CLR ligand selectivity through allosteric effects and direct peptide contacts.
A Youth Compendium of Physical Activities (Youth Compendium) was developed to estimate the energy costs of physical activities using data on youth only.
On the basis of a literature search and pooled ...data of energy expenditure measurements in youth, the energy costs of 196 activities were compiled in 16 activity categories to form a Youth Compendium of Physical Activities. To estimate the intensity of each activity, measured oxygen consumption (V˙O2) was divided by basal metabolic rate (Schofield age-, sex-, and mass-specific equations) to produce a youth MET (METy). A mixed linear model was developed for each activity category to impute missing values for age ranges with no observations for a specific activity.
This Youth Compendium consists of METy values for 196 specific activities classified into 16 major categories for four age-groups, 6-9, 10-12, 13-15, and 16-18 yr. METy values in this Youth Compendium were measured (51%) or imputed (49%) from youth data.
This Youth Compendium of Physical Activities uses pediatric data exclusively, addresses the age dependency of METy, and imputes missing METy values and thus represents advancement in physical activity research and practice. This Youth Compendium will be a valuable resource for stakeholders interested in evaluating interventions, programs, and policies designed to assess and encourage physical activity in youth.
QSAR without borders Muratov, Eugene N; Bajorath, Jürgen; Sheridan, Robert P ...
Chemical Society reviews,
06/2020, Volume:
49, Issue:
11
Journal Article
Peer reviewed
Open access
Prediction of chemical bioactivity and physical properties has been one of the most important applications of statistical and more recently, machine learning and artificial intelligence methods in ...chemical sciences. This field of research, broadly known as quantitative structure-activity relationships (QSAR) modeling, has developed many important algorithms and has found a broad range of applications in physical organic and medicinal chemistry in the past 55+ years. This Perspective summarizes recent technological advances in QSAR modeling but it also highlights the applicability of algorithms, modeling methods, and validation practices developed in QSAR to a wide range of research areas outside of traditional QSAR boundaries including synthesis planning, nanotechnology, materials science, biomaterials, and clinical informatics. As modern research methods generate rapidly increasing amounts of data, the knowledge of robust data-driven modelling methods professed within the QSAR field can become essential for scientists working both within and outside of chemical research. We hope that this contribution highlighting the generalizable components of QSAR modeling will serve to address this challenge.
Background and Purpose
Receptor activity‐modifying proteins (RAMPs) define the pharmacology of the calcitonin receptor‐like receptor (CLR). The interactions of the different RAMPs with this class B ...GPCR yield high‐affinity calcitonin gene‐related peptide (CGRP) or adrenomedullin (AM) receptors. However, the mechanism for this is unclear.
Experimental Approach
Guided by receptor models, we mutated residues in the N‐terminal helix of CLR, RAMP2 and RAMP3 hypothesized to be involved in peptide interactions. These were assayed for cAMP production with AM, AM2 and CGRP together with their cell surface expression. Binding studies were also conducted for selected mutants.
Key Results
An important domain for peptide interactions on CLR from I32 to I52 was defined. Although I41 was universally important for binding and receptor function, the role of other residues depended on both ligand and RAMP. Peptide binding to CLR/RAMP3 involved a more restricted range of residues than that to CLR/RAMP1 or CLR/RAMP2. E101 of RAMP2 had a major role in AM interactions, and F111/W84 of RAMP2/3 was important with each peptide.
Conclusions and Implications
RAMP‐dependent effects of CLR mutations suggest that the different RAMPs control accessibility of peptides to binding residues situated on the CLR N‐terminus. RAMP3 appears to alter the role of specific residues at the CLR‐RAMP interface compared with RAMP1 and RAMP2.
Enzyme activity as a method for soil biochemistry and microbiology research has a long history of more than 100 years that is not widely acknowledged in terms of adherence to strict assay protocols ...and the interpretation of results. However, in the recent past, there is a growing lack of recognition of the historic advancements among researchers that use soil enzymology. Today, many papers are being published that use methods that either do not follow exact protocols as originally vetted in the research literature or individual labs use their own method that has not been optimized for pH, co-factors, substrate concentrations, or other conditions. This is of particular concern for fluorogenic substrates and microplate methods. Furthermore, there is a lack of understanding of the origin and location of a given enzyme being studied. Notably, regardless of the enzyme, it is too often assumed that enzyme activity equals microbial activity—which is not the case for most hydrolytic enzyme assays. Because as established by Douglas McLaren in the 1950s, a considerable amount of activity can come from catalytic enzymes stabilized in the soil matrix but that are no longer associated with viable cells (known as abiontic enzymes). In summary, today, many papers are using imperfect methods and/or misinterpret enzyme activity data that at a minimum confounds cross paper studies and meta-analysis. However, most importantly, lack of historical perspectives and ignoring strict protocols cause redundancy and fundamentally undermine the discipline and understanding of soil microbiology/biochemistry when enzymology methods are used.
Marine Drugs is very pleased to host a Special Issue in honour of Prof. Dr. Peter Proksch, who served as Editor in Chief for Marine Drugs from 2005 to 2009, for his excellent research contribution.
For centuries, nature has been an inspirational source for the discovery of drugs used in modern medicine. Nowadays, natural-based treatments continue to be employed for primary health care, ...particularly playing a significant role in folk medicine. In addition, we are currently observing an increasing use of natural-products-based supplements from botanical and marine sources, making their standardization and scientific validation a priority to guarantee the safety of these products. Natural products and/or synthetic derivatives using their novel structures have also been of utmost importance in drug discovery and development in several clinical areas. After a period of discreditation and reduced investment, we are now witnessing a renewed interest from the pharmaceutical industry and scientific community due to the urgent need to develop new drugs. This reprint comprises 11 original and 6 review articles dedicated to plant and marine natural products research, contributing to the scientific validation of their use and opening new perspectives in drug discovery
Fungal natural products have made important contributions to the history of human civilization. Mr. Liu Jikai has had a significant influence on the field of chemistry in fungal natural products, ...leading a large number of Chinese scholars engaged in related research. We would like to take this opportunity to thank Mr. Liu Jikai for his efforts on fungal natural products chemistry and hope that all colleagues will make great progress for the future.
We are very pleased to introduce the Book Version of our Special Issue in Molecules dedicated to the memory of the late Professor Dr. Charles D. Hufford. The issue has been a huge success, with 22 ...full-length peer-reviewed papers and a tribute by Professor Alice M.Clark. Authors, reviewers, and collaborators from many countries across the worldhave contributed to this endeavour, and we are truly grateful to all. This Special Issue isrepresentative of the broad impact that “Charlie” had on the field of bioactive naturalproducts. This Special Issue comprises papers from Professor Hufford’s former students,colleagues, and collaborators throughout the world who have utilized a wide array ofstate-of-the-art techniques to examine diverse natural sources to isolate and identify avariety of natural products with a wide spectrum of biological activities, including somenew microbial transformations and insights into bioactive molecules. Many new bioactive compounds are described and reported here for the first time. Bioactivities reportedinclude cytotoxicity, antimicrobial activity, anti-inflammatory activity, antileishmanialactivity, antitrypanosomal activity, antimalarial activity, analgesic activity, and beneficialliver activities, just to name a few. This Special Issue will undoubtedly have a lasting impact on the field of bioactive natural products, as exemplified by the career of Dr. Hufford.Lastly, without the timely and outstanding contributions from all of you, this Special Issue would not have been possible. We thank you all very much for your contributions and your time devoted to this Special Issue in memory of a special person. Finally, we express ourgratitude and thanks to the journal Molecules and their excellent team of expert reviewers for giving us the support and opportunity to make this Special Issue a huge success!
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