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Article: Sonografische Messung des Sehnervenscheiden-Durchmessers in der Höhe

Kunze, Georg

Flugmedizin · Tropenmedizin · Reisemedizin - FTR

2023 Volume 30, Issue 06, Page(s) 269–270

Language	German
Publishing date	2023-12-01
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2277004-5
ISSN	1864-175X ; 1864-4538
ISSN (online)	1864-175X
ISSN	1864-4538
DOI	10.1055/a-2169-8286
Database	Thieme publisher's database

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Article ; Online: Recent Advances in Computer-Aided Structure-Based Drug Design on Ion Channels.

Pliushcheuskaya, Palina / Künze, Georg

International journal of molecular sciences

2023 Volume 24, Issue 11

Abstract: Ion channels play important roles in fundamental biological processes, such as electric signaling in cells, muscle contraction, hormone secretion, and regulation of the immune response. Targeting ion channels with drugs represents a treatment option for ... ...

Abstract	Ion channels play important roles in fundamental biological processes, such as electric signaling in cells, muscle contraction, hormone secretion, and regulation of the immune response. Targeting ion channels with drugs represents a treatment option for neurological and cardiovascular diseases, muscular degradation disorders, and pathologies related to disturbed pain sensation. While there are more than 300 different ion channels in the human organism, drugs have been developed only for some of them and currently available drugs lack selectivity. Computational approaches are an indispensable tool for drug discovery and can speed up, especially, the early development stages of lead identification and optimization. The number of molecular structures of ion channels has considerably increased over the last ten years, providing new opportunities for structure-based drug development. This review summarizes important knowledge about ion channel classification, structure, mechanisms, and pathology with the main focus on recent developments in the field of computer-aided, structure-based drug design on ion channels. We highlight studies that link structural data with modeling and chemoinformatic approaches for the identification and characterization of new molecules targeting ion channels. These approaches hold great potential to advance research on ion channel drugs in the future.
MeSH term(s)	Humans ; Ion Channels/metabolism ; Drug Design ; Drug Discovery ; Molecular Structure ; Muscular Diseases ; Computers ; Computer-Aided Design
Chemical Substances	Ion Channels
Language	English
Publishing date	2023-05-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24119226
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Recent Advances in NMR Protein Structure Prediction with ROSETTA.

Koehler Leman, Julia / Künze, Georg

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: Nuclear magnetic resonance (NMR) spectroscopy is a powerful method for studying the structure and dynamics of proteins in their native state. For high-resolution NMR structure determination, the collection of a rich restraint dataset is necessary. This ... ...

Abstract	Nuclear magnetic resonance (NMR) spectroscopy is a powerful method for studying the structure and dynamics of proteins in their native state. For high-resolution NMR structure determination, the collection of a rich restraint dataset is necessary. This can be difficult to achieve for proteins with high molecular weight or a complex architecture. Computational modeling techniques can complement sparse NMR datasets (<1 restraint per residue) with additional structural information to elucidate protein structures in these difficult cases. The Rosetta software for protein structure modeling and design is used by structural biologists for structure determination tasks in which limited experimental data is available. This review gives an overview of the computational protocols available in the Rosetta framework for modeling protein structures from NMR data. We explain the computational algorithms used for the integration of different NMR data types in Rosetta. We also highlight new developments, including modeling tools for data from paramagnetic NMR and hydrogen-deuterium exchange, as well as chemical shifts in CS-Rosetta. Furthermore, strategies are discussed to complement and improve structure predictions made by the current state-of-the-art AlphaFold2 program using NMR-guided Rosetta modeling.
MeSH term(s)	Models, Molecular ; Proteins/chemistry ; Magnetic Resonance Spectroscopy/methods ; Magnetic Resonance Imaging ; Software ; Nuclear Magnetic Resonance, Biomolecular/methods ; Protein Conformation
Chemical Substances	Proteins
Language	English
Publishing date	2023-04-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24097835
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting biased signaling by PAR1: function and molecular mechanism of parmodulins.

Künze, Georg / Isermann, Berend

Blood

2023 Volume 141, Issue 22, Page(s) 2675–2684

Abstract: The G protein-coupled receptor (GPCR) protease-activated receptor 1 (PAR1) is a therapeutic target that was originally pursued with the aim of restricting platelet activation and the burden of cardiovascular diseases. In clinical studies, the use of ... ...

Abstract	The G protein-coupled receptor (GPCR) protease-activated receptor 1 (PAR1) is a therapeutic target that was originally pursued with the aim of restricting platelet activation and the burden of cardiovascular diseases. In clinical studies, the use of orthosteric PAR1 inhibitors was associated with an increased risk of hemorrhage, including intracranial hemorrhage. Because (1) PAR1 is expressed by various cell types, including endothelial cells, (2) conveys in mice a physiological indispensable function for vascular development during embryogenesis, and (3) is subject to biased signaling dependent on the activating proteases, orthosteric PAR1 inhibition may be associated with unwanted side effects. Alternatively, the protease-activated protein C (aPC) and its variants can promote valuable anti-inflammatory signaling via PAR1. Most recently, small molecule allosteric modulators of PAR1 signaling, called parmodulins, have been developed. Parmodulins inhibit coagulation and platelet activation yet maintain cytoprotective effects typically provoked by PAR1 signaling upon the activation by aPC. In this study, we review the discovery of parmodulins and their preclinical data, summarize the current knowledge about their mode of action, and compare the structural interaction of parmodulin and PAR1 with that of other intracellularly binding allosteric GPCR modulators. Thus, we highlight the pharmaceutical potential and challenges associated with the future development of parmodulins.
MeSH term(s)	Mice ; Animals ; Endothelial Cells/metabolism ; Receptor, PAR-1/metabolism ; Signal Transduction ; Anti-Inflammatory Agents ; Blood Coagulation ; Peptide Hydrolases/metabolism
Chemical Substances	Receptor, PAR-1 ; Anti-Inflammatory Agents ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2023-03-22
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023019775
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Article: Targeting ion channels with ultra-large library screening for hit discovery.

Melancon, Kortney / Pliushcheuskaya, Palina / Meiler, Jens / Künze, Georg

Frontiers in molecular neuroscience

2024 Volume 16, Page(s) 1336004

Abstract: Ion channels play a crucial role in a variety of physiological and pathological processes, making them attractive targets for drug development in diseases such as diabetes, epilepsy, hypertension, cancer, and chronic pain. Despite the importance of ion ... ...

Abstract	Ion channels play a crucial role in a variety of physiological and pathological processes, making them attractive targets for drug development in diseases such as diabetes, epilepsy, hypertension, cancer, and chronic pain. Despite the importance of ion channels in drug discovery, the vastness of chemical space and the complexity of ion channels pose significant challenges for identifying drug candidates. The use of
Language	English
Publishing date	2024-01-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2023.1336004
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structural basis of the activation of PPARγ by the plasticizer metabolites MEHP and MINCH

Useini, Abibe / Engelberger, Felipe / Kunze, Georg / Sträter, Norbert

Environment International. 2023 Mar., v. 173 p.107822-

2023

Abstract: Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse health effects. Via hydrolysis of one of the two ester bonds in the human body, DEHP and ... ...

Abstract	Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse health effects. Via hydrolysis of one of the two ester bonds in the human body, DEHP and DINCH form the monoesters MEHP and MINCH, respectively. Previous studies demonstrated binding of these metabolites to PPARγ and the induction of adipogenesis via this pathway. Detailed structural understanding of how these metabolites interact with PPARγ and thereby affect human health is lacking until now. We therefore characterized the binding modes of MINCH and MEHP to the ligand binding domain of PPARγ by X-ray crystallography and molecular dynamics (MD) simulations. Both compounds bind to the activating function-2 (AF-2) binding site via an interaction of the free carboxylates with the histidines 323 and 449, tyrosine 473 and serine 289. The alkyl chains form hydrophobic interactions with the tunnel next to cysteine 285. These binding modes are generally stable as demonstrated by the MD simulations and they resemble the complexation of fatty acids and their metabolites to the AF-2 site of PPARγ. Similar to the situation for these natural PPARγ agonists, the interaction of the free carboxylate groups of MEHP and MINCH with tyrosine 473 and surrounding residues stabilizes the AF-2 helix in the upward conformation. This state promotes binding of coactivator proteins and thus formation of the active complex for transcription of the specific target genes. Moreover, a comparison of the residues involved in binding of the plasticizer metabolites in vertebrate PPARγ orthologs shows that these compounds likely have similar effects in other species.
Keywords	X-ray diffraction ; adipogenesis ; cysteine ; dicarboxylic acids ; environment ; histidine ; human health ; humans ; hydrolysis ; hydrophobicity ; ligands ; metabolites ; molecular dynamics ; phthalates ; plasticizers ; serine ; tyrosine ; DEHP ; DINCH ; Peroxisome proliferator-activated receptor γ (PPARγ) ; Endocrine disruption ; Structural biology ; Crystal structure ; Molecular dynamics simulation ; AF-2 ; CV ; DLS ; hPPARγ ; LB ; LBD ; LBP ; MD ; MEHP ; MINCH ; MR ; MWCO ; PBS ; PEG ; PGC 1α ; PVC ; RMSD ; RMSF ; RXR ; SEC ; SGBS ; SVF ; 15d-PGJ2
Language	English
Dates of publication	2023-03
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2023.107822
Database	NAL-Catalogue (AGRICOLA)

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Article: Guiding protein design choices by per-residue energy breakdown analysis with an interactive web application.

Engelberger, Felipe / Zakary, Jonathan D / Künze, Georg

Frontiers in molecular biosciences

2023 Volume 10, Page(s) 1178035

Abstract: Recent developments in machine learning have greatly facilitated the design of proteins with improved properties. However, accurately assessing the contributions of an individual or multiple amino acid mutations to overall protein stability to select the ...

Abstract	Recent developments in machine learning have greatly facilitated the design of proteins with improved properties. However, accurately assessing the contributions of an individual or multiple amino acid mutations to overall protein stability to select the most promising mutants remains a challenge. Knowing the specific types of amino acid interactions that improve energetic stability is crucial for finding favorable combinations of mutations and deciding which mutants to test experimentally. In this work, we present an interactive workflow for assessing the energetic contributions of single and multi-mutant designs of proteins. The energy breakdown guided protein design (ENDURE) workflow includes several key algorithms, including per-residue energy analysis and the sum of interaction energies calculations, which are performed using the Rosetta energy function, as well as a residue depth analysis, which enables tracking the energetic contributions of mutations occurring in different spatial layers of the protein structure. ENDURE is available as a web application that integrates easy-to-read summary reports and interactive visualizations of the automated energy calculations and helps users selecting protein mutants for further experimental characterization. We demonstrate the effectiveness of the tool in identifying the mutations in a designed polyethylene terephthalate (PET)-degrading enzyme that add up to an improved thermodynamic stability. We expect that ENDURE can be a valuable resource for researchers and practitioners working in the field of protein design and optimization. ENDURE is freely available for academic use at: http://endure.kuenzelab.org.
Language	English
Publishing date	2023-05-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1178035
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structural basis of the activation of PPARγ by the plasticizer metabolites MEHP and MINCH.

Useini, Abibe / Engelberger, Felipe / Künze, Georg / Sträter, Norbert

Environment international

2023 Volume 173, Page(s) 107822

Abstract	Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse health effects. Via hydrolysis of one of the two ester bonds in the human body, DEHP and DINCH form the monoesters MEHP and MINCH, respectively. Previous studies demonstrated binding of these metabolites to PPARγ and the induction of adipogenesis via this pathway. Detailed structural understanding of how these metabolites interact with PPARγ and thereby affect human health is lacking until now. We therefore characterized the binding modes of MINCH and MEHP to the ligand binding domain of PPARγ by X-ray crystallography and molecular dynamics (MD) simulations. Both compounds bind to the activating function-2 (AF-2) binding site via an interaction of the free carboxylates with the histidines 323 and 449, tyrosine 473 and serine 289. The alkyl chains form hydrophobic interactions with the tunnel next to cysteine 285. These binding modes are generally stable as demonstrated by the MD simulations and they resemble the complexation of fatty acids and their metabolites to the AF-2 site of PPARγ. Similar to the situation for these natural PPARγ agonists, the interaction of the free carboxylate groups of MEHP and MINCH with tyrosine 473 and surrounding residues stabilizes the AF-2 helix in the upward conformation. This state promotes binding of coactivator proteins and thus formation of the active complex for transcription of the specific target genes. Moreover, a comparison of the residues involved in binding of the plasticizer metabolites in vertebrate PPARγ orthologs shows that these compounds likely have similar effects in other species.
MeSH term(s)	Humans ; Plasticizers/metabolism ; Diethylhexyl Phthalate/toxicity ; Diethylhexyl Phthalate/metabolism ; PPAR gamma/metabolism ; Furylfuramide ; Phthalic Acids/metabolism
Chemical Substances	Plasticizers ; mono-(2-ethylhexyl)phthalate (FU2EWB60RT) ; Diethylhexyl Phthalate (C42K0PH13C) ; PPAR gamma ; Furylfuramide (054NR2135Y) ; Phthalic Acids
Language	English
Publishing date	2023-02-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2023.107822
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Article ; Online: Improving the Modeling of Extracellular Ligand Binding Pockets in RosettaGPCR for Conformational Selection.

Liessmann, Fabian / Künze, Georg / Meiler, Jens

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: G protein-coupled receptors (GPCRs) are the largest class of drug targets and undergo substantial conformational changes in response to ligand binding. Despite recent progress in GPCR structure determination, static snapshots fail to reflect the ... ...

Abstract	G protein-coupled receptors (GPCRs) are the largest class of drug targets and undergo substantial conformational changes in response to ligand binding. Despite recent progress in GPCR structure determination, static snapshots fail to reflect the conformational space of putative binding pocket geometries to which small molecule ligands can bind. In comparative modeling of GPCRs in the absence of a ligand, often a shrinking of the orthosteric binding pocket is observed. However, the exact prediction of the flexible orthosteric binding site is crucial for adequate structure-based drug discovery. In order to improve ligand docking and guide virtual screening experiments in computer-aided drug discovery, we developed RosettaGPCRPocketSize. The algorithm creates a conformational ensemble of biophysically realistic conformations of the GPCR binding pocket between the TM bundle, which is consistent with a knowledge base of expected pocket geometries. Specifically, tetrahedral volume restraints are defined based on information about critical residues in the orthosteric binding site and their experimentally observed range of C
MeSH term(s)	Ligands ; Binding Sites ; Receptors, G-Protein-Coupled/metabolism ; Molecular Conformation ; Drug Discovery/methods ; Protein Binding ; Protein Conformation
Chemical Substances	Ligands ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2023-04-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24097788
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Article: Anwendung der Sonografie auch für Expeditionsärzte interessant

Kunze, Georg

Flugmedizin · Tropenmedizin · Reisemedizin - FTR

2019 Volume 26, Issue 04, Page(s) 150–151

Abstract: Mithilfe der Thorax- beziehungsweise der Lungensonografie (LUS) können nahezu alle Lungenerkrankungen mit Ausnahme der COPD und des Emphysems diagnostiziert werden, sofern sie sich in irgendeiner Form an der sonografisch darstellbaren Lungenoberfläche ... ...

Abstract	Mithilfe der Thorax- beziehungsweise der Lungensonografie (LUS) können nahezu alle Lungenerkrankungen mit Ausnahme der COPD und des Emphysems diagnostiziert werden, sofern sie sich in irgendeiner Form an der sonografisch darstellbaren Lungenoberfläche widerspiegeln 1. Der deutlich vermehrte Nachweis von sogenannten B-Lines (Artefakte, die sich von der unauffälligen Lungenoberfläche bis an den Unterrand des Bildschirms erstrecken und sich atemsynchron bewegen) gilt als Korrelat für ein interstitielles Ödem und wird bereits auf vielen Intensivstationen und in Notaufnahmen zur bettseitigen Diagnose eines Lungenödems verwendet 2.:
Language	German
Publishing date	2019-08-01
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2277004-5
ISSN	1864-175X ; 1864-4538
ISSN (online)	1864-175X
ISSN	1864-4538
DOI	10.1055/a-0971-3204
Database	Thieme publisher's database

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