Science
Kobilka: “Structural insights into the dynamic process of G protein-coupled receptor activation.”
Dr. Brian Kobilka, the co-recipient of the 2012 Nobel Prize in Chemistry, spoke at the UW Health Sciences Center on Tuesday, Oct. 23.
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There are more than 1000 GPCRs, and they are involved in transduction of light, neurotransmitter, chemical, and hormone signals. GPCRs are an important target for drugs because their involvement in so many physiological functions . Kobilka’s work in GPCR structure and function has advanced our understanding of this complex family of receptors.
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2012 Nobel Laureate in Chemistry Brian Kobilka will speak at UW …Oct 18, 2012 … Dr. Brian Kobilka, the co-recipient of the 2012 Nobel Prize in Chemistry, will speak at the UW Health Sciences Center …
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Chemistry Nobel Prize Brian Kobilka at UW. GPCR activation talk to start in a few minutes #ChemNobel2012 -
Standing room only in Hogness! #kobilkaseminar -
Dr. Kobilka was originally scheduled to speak in front of a reduced audience at the University of Washington Biochemistry weekly seminar series. After receiving the Nobel price in October 10th the venue changed to Hogness (capacity 482 seats).
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Brian Kobilka: I have never spoken in front of this many people before. UW Hogness Auditorium #ChemNobel2012
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Kobilka described the challenges of obtaining a protein crystal to study the structure for G-protein coupled receptors.
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First b2ar xtal a only diffracted to 20 A #kobilkaseminar
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Brian Kobilka – ScienceWatch.com
The author has also sent along images of their work. Brian Kobilka, Article Title: High-resolution crystal structure of an engineered h… -
Beta-2 Adrenergic Receptor – Proteopedia, life in 3DOct 15, 2012 … Click on the green links: they change the 3D image. … The structure of B2AR is very similar to the GPCR Rhodopsin, w…
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He also talk about his recent work on the structure of b2 adrenaline
receptor: “Recent crystal structures provide insights into inactive
states of several GPCRs. Efforts to obtain an agonist-bound active-state
GPCR structure have proven difficult due to the inherent instability of
this state in the absence of a G protein. We generated a camelid
antibody fragment (nanobody) to the human b2 adrenergic receptor (b2AR)
that exhibits G protein-like behaviour, and obtained an agonist-bound,
active-state crystal structure of the receptor-nanobody complex”
(Rasmussen et al. Nature 2011) -
Nanobodies (variable region Ab from camelids) FTW! #kobilkaseminar
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Kobilka: Nanobodies from Llamas key for getting stable structure of our GPCR. We can track structural changes in GPCR cycle #ChemNobel2012
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ß2AR in several states. Agonist makes it more inestable, only G-protein stabilizes it in one state #Kobilkaseminar #ChemNobel2012
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Change in binding pocket of b2ar depends on g-protein coupling – not necessarily the ligand #kobilkaseminar
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From 2011 Nature paper: “Comparison with the inactive b2AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11A˚ outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.”
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3sn6 – Proteopedia, life in 3DOct 20, 2012 … Publication Abstract from PubMed. G protein-coupled receptors (GPCRs) are responsible for the majority of cellular res…
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Small changes in binding pocket when ligand binds, big changes in TM helices #b2AR #kobilkaseminar
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Coupling between ligand binding and allosteric change pretty weak – dynamics #b2AR #kobilkaseminar
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Very strong agonists increase heterogeneity, unless there is nanobody bound #b2AR #kobilkaseminar
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Dynamic aspect of ß2AR may explain its functional versatility #KobilkaSeminar #ChemNobel2012
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From Kobilka’s lab: “The method that we developed to obtain crystals of the beta2AR
(generating T4 lysozyme fusion proteins) has subsequently been used to
crystallize twelve other GPCRs including the following structures from
our lab: the M2 and M3 muscarinic receptors, the mu- and delta-opioid
receptors, and the protease activated receptor (PAR1). These structures
all represent inactive states of these GPCRs.” -
Moving on to muscarinic and opioid receptors #kobilkaseminar
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Muscarinic receptors have VERY closed binding pockets. #kobilkaseminar
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Efficacy determinants deep in pocket, conserved. Selectivity determinants more exposed #opiodreceptor #kobilkaseminar
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The muscarinic receptors don’t have accessible selectivity determinants. That makes it harder to develop drugs #kobilkaseminar
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Selectivity determinants that distinguish b2ar from b1ar also toward extraellular vestibule #kobilkaseminar
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Can explain selectivity of salmeterol by structure #kobilkaseminar
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Vestibular interactions influence selectivity, even if the ligand doesn’t contact those residues. #kobilkaseminar
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Muscarinic ligands also spend a long time hanging out by the extraellular residues. May be I pt for drug development #kobilkaseminar
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That was fun! #kobilkaseminar
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Q&A #KobilkaSeminar: how do you know structures reflect real states? functional data, many structures show coherent picture #ChemNobel2012
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Additional links:
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Brian K. Kobilka – Interview – Nobelprize.org
Oct 10, 2012 … Nobelprize.org. Portraits of the 2012 Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel, Flag of … -
The Nobel Prize in Chemistry 2012 – Prize … – Nobelprize.org
Oct 10, 2012 … Nobelprize.org. Portraits of the 2012 Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel, Flag of …
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G Protein-Coupled Receptors (GPCRs) win 2012 Nobel Prize in …
Oct 10, 2012 … Ashutosh Jogalekar Ashutosh (Ash) Jogalekar is a chemist interested in the history and philosophy of science. He consi…
