präsentationstitel in arial bold kann auch dreizeilig sein ... · neurobiology. molecular switches...
TRANSCRIPT
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MOLECULAR SWITCHES
Seminar Bioorganik (WS18/19)
Leipzig, 28.01.2019
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INTRODUCTION
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Molecular switches
OPTOGENETICS
3
= technique to control cells in living tissue (typically
neurons) by light
Cells were genetically modified to express light-sensitive
ion channels
Optochemical genetics → addition of a chemical
component
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Molecular switches
4
transmembrane proteins, sensitive to an input signal:
Light intensity
Pressure
Voltage
Temperature
Ligand concentration
all can be influenced by ligands (e.g. channel blockers)
→ point of contact for optochemical genetics
TRANSMEMBRANE RECEPTORS IN
NEUROBIOLOGY
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Molecular switches
TRANSMEMBRANE RECEPTORS IN NEUROBIOLOGY
5
Activated by / ligand / voltage
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Molecular switches
NEUROTRANSMISSION
6
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Molecular switches
CHANNELRHODOPSIN-2
7
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Molecular switches
LIGHTING UP THE BRAIN – LIGHT-SENSITIVE
RECEPTORS
8
→ Optogenetics
Fast modulation of intensity within femtoseconds
Can be focused onto very small areas
Carry enough energy to trigger larger molecular motions
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MOLECULAR TOOLS
IN OPTOCHEMICAL
GENETICS
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Molecular switches
CAGED LIGAND APPROACH (CL)
10
Simplest and oldest approach
first shown in living animals
Irreversible process and produces by-products
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Molecular switches
PHOTOCHROMIC LIGAND APPROACH (PCL)
11
Ease of application, fast distribution → good as drugs
Work well in complex systems
Selectivity between receptor subtypes is challenging
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Molecular switches
PHOTOSWITCHED TETHERED LIGAND
APPROACH (PTL)
12
Selectivity between receptor subtypes
Can be genetically encoded → biologic, not synthetic
Ligand does not need high affinity
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Molecular switches
PTL – FUNKTIONAL DISSECTION OF RELATED
RECEPTOR SUBTYPES
13
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Molecular switches
AZOBENZENE PHOTOSWITCHES
14
Fast, photostable, need low intensity
Easy to synthesize and modify
Low solubility → overcome with functional groups
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VOLTAGE-GATED
POTASSIUM
CHANNELS
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Molecular switches
VOLTAGE-GATED POTASSIUM CHANNELS
Modulate cellular excitability
Play a key role in the generation of action potentials
16
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Molecular switches
VOLTAGE-GATED POTASSIUM CHANNELS
Channel blockers
Cs+ ions
Venom peptides
Small organic cations
External TEA
Internal TEA
17TEA: tetraethylammonium
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Molecular switches
PHOTOSENSITIZING VOLTAGE-GATED
POTASSIUM CHANNELS
PTL approach
H-SPARK
Hyperpolarizing effect
18SPARK: Synthetic photoisomerizable azobenzene-regulated K+ channel
MAQ: maleimide/azobenzene/quartenary/ammonium
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Molecular switches
PHOTOSENSITIZING VOLTAGE-GATED
POTASSIUM CHANNELS
PTL approach
D-SPARK
Depolarizing effect
19SPARK: Synthetic photoisomerizable azobenzene-regulated K+ channel
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Molecular switches
PHOTOSENSITIZING VOLTAGE-GATED
POTASSIUM CHANNELS
PCL approach
XAQs
20
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Molecular switches
PHOTOSENSITIZING VOLTAGE-GATED
POTASSIUM CHANNELS
Shift the absorption and action spectra toward the red
deeper tissue penetration
diminish the phototoxity
21
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IONOTROPIC
GLUTAMATE
RECEPTORS
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Molecular switches
IONOTROPIC GLUTAMATE RECEPTORS
Play a cenral role in synaptic transmission
Antagonists
„foot-in-the-door“ mechanism
23
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Molecular switches
PHOTOSENSITIZING IONOTROPIC GLUTAMATE
RECEPTORS
PTL approach
LiGluR
24LiGluR: light-gated ionotropic receptor
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Molecular switches
PHOTOSENSITIZING IONOTROPIC GLUTAMATE
RECEPTORS
Sign inversion
MAG-0 is attached to
25
cis activation
trans activation
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Molecular switches
PHOTOSENSITIZING IONOTROPIC GLUTAMATE
RECEPTORS
HyLighter
26
K+ selective TMD of the
procaroytic glutamate
receptor
Photosensitive LBD of
LiGluR
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Molecular switches
PHOTOSENSITIZING IONOTROPIC GLUTAMATE
RECEPTORS
Controlling the escape reflex in zebrafish
27
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Molecular switches
PHOTOSENSITIZING IONOTROPIC GLUTAMATE
RECEPTORS
PCL approach
28
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PENTAMERIC LIGAND-
GATED ION CHANNELS
29
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Molecular switches
SUBGROUPS
Nicotinic acetylcholine receptor (nAChR)
γ-aminobutyric acid receptors (GABAA/C)
5-hydroxytryptamine receptors (5-HT3)
glycine receptors (GlyRs)
30
acetylcholine
GABA
serotonin
glycine
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Molecular switches
NICOTINIC ACETYLCHOLINE RECEPTOR
31Source: Nasiripourdori, A.; et al.: From Toxins Targeting Ligand Gated Ion
Channels to Therapeutic Molecules. Toxins. December 2011, 3:260-293
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Molecular switches
Source:
NICOTINIC ACETYLCHOLINE RECEPTOR
32
• first photosensitized
receptor
• easy accessable in
certain fishes
acetylcholine
or
nicotin
Electrophoruselectricus
Source: https://de.wikipedia.org/wiki/Zitteraal#/media/File:Electrophorus_electricus_3.jpg,
18.01.19
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Molecular switches
PHOTOSENSITIZING OF NICOTINIC
ACETYLCHOLINE RECEPTOR
33
PCL
PTL
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OUTLOOK
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Molecular switches
ALTERNATIVE AND FUTURE TARGETS FOR
PHOTOSENSITIZING
• countless receptors
• taste and olfactory receptors, GPCRs, etc.
• receptor linked enzymes
• e. g. receptor tyrosine kinases
• receptor agonists and antagonists
35
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Molecular switches
PHOTOACTIVATABLE CHEMOKINES
36Source: Baumann, L.; Beck-Sickinger, A. G.: Photoactivatable Chemokines – Controlling Protein
Activity by Light. Angewandte Chemie. June 2013, Volume 52, Issue 36
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Molecular switches
FUTURE TASKS AND UTILISATIONS
• phoswitchable cross-linkers
• exploring of new photoswitchers
• switchers sensitive für other signals
• orthogonal ligands
• electromagnetic fields
• knock-in instead of knock-out
mutants
37Source: Valeur, E.; et al.: New Modalities for Challenging Targets in Drug Discovery. Angewandte
Chemie. February 2017, Volume 56, Issue 35
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Molecular switches
CURING BLINDNESS
38Source: https://www.allaboutvision.com/resources/retina.htm (20.01.19)
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THANK YOU FOR YOUR
ATTENTION!