4lde: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of beta2 adrenoceptor bound to BI167107 and an engineered nanobody== | |||
<StructureSection load='4lde' size='340' side='right' caption='[[4lde]], [[Resolution|resolution]] 2.79Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4lde]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LDE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LDE FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1WV:(2S)-2,3-DIHYDROXYPROPYL+(7Z)-TETRADEC-7-ENOATE'>1WV</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=P0G:8-[(1R)-2-{[1,1-DIMETHYL-2-(2-METHYLPHENYL)ETHYL]AMINO}-1-HYDROXYETHYL]-5-HYDROXY-2H-1,4-BENZOXAZIN-3(4H)-ONE'>P0G</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ldl|4ldl]], [[4ldo|4ldo]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, E, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4lde FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lde OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lde RCSB], [http://www.ebi.ac.uk/pdbsum/4lde PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/LYS_BPT4 LYS_BPT4]] Helps to release the mature phage particles from the cell wall by breaking down the peptidoglycan. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
G-protein-coupled receptors (GPCRs) are integral membrane proteins that have an essential role in human physiology, yet the molecular processes through which they bind to their endogenous agonists and activate effector proteins remain poorly understood. So far, it has not been possible to capture an active-state GPCR bound to its native neurotransmitter. Crystal structures of agonist-bound GPCRs have relied on the use of either exceptionally high-affinity agonists or receptor stabilization by mutagenesis. Many natural agonists such as adrenaline, which activates the beta2-adrenoceptor (beta2AR), bind with relatively low affinity, and they are often chemically unstable. Using directed evolution, we engineered a high-affinity camelid antibody fragment that stabilizes the active state of the beta2AR, and used this to obtain crystal structures of the activated receptor bound to multiple ligands. Here we present structures of the active-state human beta2AR bound to three chemically distinct agonists: the ultrahigh-affinity agonist BI167107, the high-affinity catecholamine agonist hydroxybenzyl isoproterenol, and the low-affinity endogenous agonist adrenaline. The crystal structures reveal a highly conserved overall ligand recognition and activation mode despite diverse ligand chemical structures and affinities that range from 100 nM to approximately 80 pM. Overall, the adrenaline-bound receptor structure is similar to the others, but it has substantial rearrangements in extracellular loop three and the extracellular tip of transmembrane helix 6. These structures also reveal a water-mediated hydrogen bond between two conserved tyrosines, which appears to stabilize the active state of the beta2AR and related GPCRs. | |||
Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody.,Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK Nature. 2013 Oct 24;502(7472):575-9. doi: 10.1038/nature12572. Epub 2013 Sep 22. PMID:24056936<ref>PMID:24056936</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Adrenergic receptor|Adrenergic receptor]] | |||
*[[Antibody|Antibody]] | |||
*[[Lysozyme 3D structures|Lysozyme 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Lama glama]] | [[Category: Lama glama]] | ||
[[Category: Lysozyme]] | [[Category: Lysozyme]] | ||
[[Category: Enos, M D | [[Category: Enos, M D]] | ||
[[Category: Garcia, K C | [[Category: Garcia, K C]] | ||
[[Category: Kobilka, B K | [[Category: Kobilka, B K]] | ||
[[Category: Kruse, A C | [[Category: Kruse, A C]] | ||
[[Category: Manglik, A | [[Category: Manglik, A]] | ||
[[Category: Ring, A M | [[Category: Ring, A M]] | ||
[[Category: Weis, W I | [[Category: Weis, W I]] | ||
[[Category: G protein coupled receptor]] | [[Category: G protein coupled receptor]] | ||
[[Category: Membrane protein-hydrolase complex]] | [[Category: Membrane protein-hydrolase complex]] | ||
Revision as of 14:53, 25 December 2014
Structure of beta2 adrenoceptor bound to BI167107 and an engineered nanobodyStructure of beta2 adrenoceptor bound to BI167107 and an engineered nanobody
Structural highlights
Function[LYS_BPT4] Helps to release the mature phage particles from the cell wall by breaking down the peptidoglycan. Publication Abstract from PubMedG-protein-coupled receptors (GPCRs) are integral membrane proteins that have an essential role in human physiology, yet the molecular processes through which they bind to their endogenous agonists and activate effector proteins remain poorly understood. So far, it has not been possible to capture an active-state GPCR bound to its native neurotransmitter. Crystal structures of agonist-bound GPCRs have relied on the use of either exceptionally high-affinity agonists or receptor stabilization by mutagenesis. Many natural agonists such as adrenaline, which activates the beta2-adrenoceptor (beta2AR), bind with relatively low affinity, and they are often chemically unstable. Using directed evolution, we engineered a high-affinity camelid antibody fragment that stabilizes the active state of the beta2AR, and used this to obtain crystal structures of the activated receptor bound to multiple ligands. Here we present structures of the active-state human beta2AR bound to three chemically distinct agonists: the ultrahigh-affinity agonist BI167107, the high-affinity catecholamine agonist hydroxybenzyl isoproterenol, and the low-affinity endogenous agonist adrenaline. The crystal structures reveal a highly conserved overall ligand recognition and activation mode despite diverse ligand chemical structures and affinities that range from 100 nM to approximately 80 pM. Overall, the adrenaline-bound receptor structure is similar to the others, but it has substantial rearrangements in extracellular loop three and the extracellular tip of transmembrane helix 6. These structures also reveal a water-mediated hydrogen bond between two conserved tyrosines, which appears to stabilize the active state of the beta2AR and related GPCRs. Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody.,Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK Nature. 2013 Oct 24;502(7472):575-9. doi: 10.1038/nature12572. Epub 2013 Sep 22. PMID:24056936[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||