PD Dr. Richard Alfred Kammerer

Group Leader
Paul Scherrer Institute
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Telefon
E-Mail
Research Interests
Botulinum neurotoxin A (BoNT/A), commonly known as Botox, is the most toxic substance known and causes human botulism, a rare but potentially fatal paralytic disease. Despite its toxicity, BoNT/A is used as an effective therapeutic for the treatment of a wide range of neuronal and neuromuscular disorders. BoNT/A is probably best known for its application as an anti-wrinkle agent. A detailed molecular understanding of BoNT/host protein interactions is fundamental both for developing strategies against botulism and for generating improved BoNT variants for medical applications. Towards this aim, we have recently determined a crystal structure of BoNT/A in complex with its protein receptor synaptic vesicle glycoprotein 2C (SV2C). The complex crystal structure has important implications for BoNT/A function.
G-protein coupled receptors (GPCRs) are integral membrane proteins that share a common seven-transmembrane helix fold topology. They play fundamental roles in most physiological and many pathological processes. Currently, GPCRs are the target of ~30% of all medical drugs. As a result of the major drug discovery activities targeting GPCRs, there is a growing demand for high-resolution structures. Despite enormous efforts, however, progress in the structural characterization of GPCRs is rather slow. Primarily two methods have been developed for structural work on GPCRs: scanning alanine mutagenesis and the fusion protein engineering approach. However, both methods have substantial limitations, emphasizing that the development of new GPCR crystallization tools will be of fundamental importance in moving the field forward. Towards this aim, we developed a novel approach to facilitate the crystallization of GPCRs.
The overarching aims of our research are to understand BoNT/A-host protein interactions at the molecular detail and to develop new GPCR crystallization tools. For our studies, we use biochemical, biophysical and structural biological techniques.
G-protein coupled receptors (GPCRs) are integral membrane proteins that share a common seven-transmembrane helix fold topology. They play fundamental roles in most physiological and many pathological processes. Currently, GPCRs are the target of ~30% of all medical drugs. As a result of the major drug discovery activities targeting GPCRs, there is a growing demand for high-resolution structures. Despite enormous efforts, however, progress in the structural characterization of GPCRs is rather slow. Primarily two methods have been developed for structural work on GPCRs: scanning alanine mutagenesis and the fusion protein engineering approach. However, both methods have substantial limitations, emphasizing that the development of new GPCR crystallization tools will be of fundamental importance in moving the field forward. Towards this aim, we developed a novel approach to facilitate the crystallization of GPCRs.
The overarching aims of our research are to understand BoNT/A-host protein interactions at the molecular detail and to develop new GPCR crystallization tools. For our studies, we use biochemical, biophysical and structural biological techniques.
Group Members

Mara Wieser
Technician
Publications
2018
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Structural Basis of Formation of the Microtubule Minus-End-Regulating CAMSAP-Katanin Complex
STRUCTURE -, S0969212617304422 (2018).DOI: 10.1016/j.str.2017.12.017
2017
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Baculovirus-based genome editing in primary cells
PLASMID 90, 5 (2017).DOI: 10.1016/j.plasmid.2017.01.003
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Comprehensive Analysis of the Role of Arrestin Residues in Receptor Binding
Springer International Publishing -, 83 (2017).DOI: 10.1007/978-3-319-57553-7_7
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Crystal structure of the BoNT/A2 receptor-binding domain in complex with the luminal domain of its neuronal receptor SV2C
Scientific Reports 7, 43588 (2017).DOI: 10.1038/srep43588
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Microtubule minus-end regulation at spindle poles by an ASPM-katanin complex.
NATURE CELL BIOLOGY 19, 480 (2017).DOI: 10.1038/NCB3511
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Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 114, E9821 (2017).DOI: 10.1073/PNAS.1712621114
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Short Linear Sequence Motif LxxPTPh Targets Diverse Proteins to Growing Microtubule Ends.
STRUCTURE 25, 924 (2017).DOI: 10.1016/J.STR.2017.04.010
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Structural basis of katanin p60:p80 complex formation
Scientific Reports 7, 14893 (2017).DOI: 10.1038/s41598-017-14194-2
2016
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Accelerating the Association of the Most Stable Protein-Ligand Complex by more than Two Orders of Magnitude
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION , (2016).DOI: 10.1002/anie.201603652
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Biophysical and Structural Characterization of the Centriolar Protein Cep104 Interaction Network.
JOURNAL OF BIOLOGICAL CHEMISTRY 291, 18496 (2016).DOI: 10.1074/JBC.M116.739771
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Centriolar CPAP/SAS-4 Imparts Slow Processive Microtubule Growth
DEVELOPMENTAL CELL 37, 362-376 (2016).DOI: 10.1016/j.devcel.2016.04.024
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SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture
NATURE CELL BIOLOGY 18, 393-+ (2016).DOI: 10.1038/ncb3329
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Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations
Scientific Reports 6, 30668 (2016).DOI: 10.1038/srep30668
2015
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Functional roles of the hexamer organization of plant glutamate decarboxylase
BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - PROTEINS AND PROTEOMICS 1854, 1229 (2015).DOI: 10.1016/j.bbapap.2015.01.001
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Structure of the BoNT/A1 - receptor complex
TOXICON 107, 25 (2015).DOI: 10.1016/j.toxicon.2015.08.002
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Time-resolved structural studies with serial crystallography: A new light on retinal proteins
STRUCTURAL DYNAMICS 2, 041718 (2015).DOI: 10.1063/1.4922774
2014
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7 angstrom resolution in protein two-dimensional-crystal X-ray diffraction at Linac Coherent Light Source
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES 369, UNSP 20130500 (2014).DOI: 10.1098/rstb.2013.0500
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A Type IV Translocated Legionella Cysteine Phytase Counteracts Intracellular Growth Restriction by Phytate
JOURNAL OF BIOLOGICAL CHEMISTRY 289, 34175-34188 (2014).DOI: 10.1074/jbc.M114.592568
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Conformational transitions driven by pyridoxal-5 '-phosphate uptake in the psychrophilic Serine hydroxymethyltransferase from Psychromonas ingrahamii
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS 82, 2831-2841 (2014).DOI: 10.1002/prot.24646
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Coronin 1 Regulates Cognition and Behavior through Modulation of cAMP/Protein Kinase A Signaling
PLOS BIOLOGY 12, e1001820 (2014).DOI: 10.1371/journal.pbio.1001820
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How Periplasmic Thioredoxin TlpA Reduces Bacterial Copper Chaperone ScoI and Cytochrome Oxidase Subunit II (CoxB) Prior to Metallation
JOURNAL OF BIOLOGICAL CHEMISTRY 289, (2014).DOI: 10.1074/jbc.M114.607127
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Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A
NATURE 505, 108-+ (2014).DOI: 10.1038/nature12732
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Structural basis for-10 promoter element melting by environmentally induced sigma factors
NATURE STRUCTURAL & MOLECULAR BIOLOGY 21, 269-276 (2014).DOI: 10.1038/nsmb.2777
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Structure, Activity, and Stability of Atomically Dispersed Rh in Methane Steam Reforming
ACS CATALYSIS 4, 1279 (2014).DOI: 10.1021/cs400979q
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Transient Mechanistic Studies of Methane Steam Reforming over Ceria-Promoted Rh/Al2O3 Catalysts
CHEMCATCHEM 6, 2898 (2014).DOI: 10.1002/cctc.201402388
2013
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(4R)- and (4S)-Fluoroproline in the Conserved cis-Prolyl Peptide Bond of the Thioredoxin Fold: Tertiary Structure Context Dictates Ring Puckering
CHEMBIOCHEM 14, 1053-1057 (2013).DOI: 10.1002/cbic.201300178
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Quaternary Dynamics of the SecA Motor Drive Translocase Catalysis
MOLECULAR CELL 52, 655-666 (2013).DOI: 10.1016/j.molcel.2013.10.036
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Structural Basis for the Oligomerization-State Switch from a Dimer to a Trimer of an Engineered Cortexillin-1 Coiled-Coil Variant
PLOS ONE 8, e63370 (2013).DOI: 10.1371/journal.pone.0063370
2011
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A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo: Implication for Treating Hyperproliferative Disorders
PLOS ONE 6, e22436 (2011).DOI: 10.1371/journal.pone.0022436
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Integration of multiple expression cassettes into mammalian genomes in a single step
Protocol Exchange , (2011).DOI: 10.1038/protex.2011.249
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RNA polymerase I?specific subunits promote polymerase clustering to enhance the rRNA gene transcription cycle
The Journal of Cell Biology 192, 277 (2011).DOI: 10.1083/jcb.201006040
2010
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Automated seamless DNA co-transformation cloning with direct expression vectors applying positive or negative insert selection
BMC BIOTECHNOLOGY 10, 56 (2010).DOI: 10.1186/1472-6750-10-56
2009
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Automated unrestricted multigene recombineering for multiprotein complex production
NATURE METHODS 6, 447 (2009).DOI: 10.1038/nmeth.1326
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Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models
NEUROGENETICS 10, 275 (2009).DOI: 10.1007/s10048-009-0183-3
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Mutation of His465 Alters the pH-dependent Spectroscopic Properties of Escherichia coli Glutamate Decarboxylase and Broadens the Range of Its Activity toward More Alkaline pH
JOURNAL OF BIOLOGICAL CHEMISTRY 284, 31587 (2009).DOI: 10.1074/jbc.M109.049577
2008
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Anti-Mullerian-hormone-dependent regulation of the brain serine-protease inhibitor neuroserpin
JOURNAL OF CELL SCIENCE 121, 3357 (2008).DOI: 10.1242/jcs.031872
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Crystal structure of the ternary FimC-FimF(t)-FimD(N) complex indicates conserved pilus chaperone-subunit complex recognition by the usher FimD
FEBS LETTERS 582, 651 (2008).DOI: 10.1016/j.febslet.2008.01.030
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Molecular evolution of B6 enzymes: Binding of pyridoxal-5'-phosphate and Lys41Arg substitution turn ribonuclease A into a model B6 protoenzyme
BMC BIOCHEMISTRY 9, 17 (2008).DOI: 10.1186/1471-2091-9-17
2007
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Mtmr13/Sbf2-deficient mice: an animal model for CMT4B2
HUMAN MOLECULAR GENETICS 16, 2991 (2007).DOI: 10.1093/hmg/ddm257
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Multiprotein Expression Strategy for Structural Biology of Eukaryotic Complexes
STRUCTURE 15, 275 (2007).DOI: 10.1016/j.str.2007.01.016
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Production of in vitro amplified DNA pseudolibraries and high-throughput cDNA target amplification
BMC BIOTECHNOLOGY 7, 31 (2007).DOI: 10.1186/1472-6750-7-31
2006
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Multi-level regulation of myotubularin-related protein-2 phosphatase activity by myotubularin-related protein-13/set-binding factor-2
HUMAN MOLECULAR GENETICS 15, 569 (2006).DOI: 10.1093/hmg/ddi473
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Pathomechanisms of mutant proteins in Charcot-Marie-Tooth disease
NEUROMOLECULAR MEDICINE 8, 217 (2006).DOI: 10.1385/NMM:8:1:217
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Protein complex expression by using multigene baculoviral vectors
NATURE METHODS 3, 1021 (2006).DOI: 10.1038/nmeth983
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Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease)
GLIA 54, 243 (2006).DOI: 10.1002/glia.20386
2004
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COMP-Ang1: A designed angiopoietin-1 variant with nonleaky angiogenic activity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 101, 5547-5552 (2004).DOI: 10.1073/pnas.0307574101