6mxt

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Crystal structure of human beta2 adrenergic receptor bound to salmeterol and Nb71

Structural highlights

6mxt is a 2 chain structure with sequence from Escherichia virus T4, Homo sapiens and Lama glama. This structure supersedes the now removed PDB entry 6csy. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.9593422Å
Ligands:HTO, K5Y, MG, NI, OLA, OLC, P33, YCM
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ADRB2_HUMAN Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.ENLYS_BPT4 Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[1]

Publication Abstract from PubMed

Salmeterol is a partial agonist for the beta2 adrenergic receptor (beta2AR) and the first long-acting beta2AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol's safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound beta2AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between beta1AR and beta2AR explain the high receptor-subtype selectivity. A structural comparison with the beta2AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser204(5.43) and Asn293(6.55). Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited beta-arrestin recruitment for salmeterol.

Structural insights into binding specificity, efficacy and bias of a beta2AR partial agonist.,Masureel M, Zou Y, Picard LP, van der Westhuizen E, Mahoney JP, Rodrigues JPGLM, Mildorf TJ, Dror RO, Shaw DE, Bouvier M, Pardon E, Steyaert J, Sunahara RK, Weis WI, Zhang C, Kobilka BK Nat Chem Biol. 2018 Nov;14(11):1059-1066. doi: 10.1038/s41589-018-0145-x. Epub, 2018 Oct 16. PMID:30327561[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Moussa SH, Kuznetsov V, Tran TA, Sacchettini JC, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012 Apr;21(4):571-82. doi: 10.1002/pro.2042. Epub 2012 Mar 2. PMID:22389108 doi:http://dx.doi.org/10.1002/pro.2042
  2. ↑ Masureel M, Zou Y, Picard LP, van der Westhuizen E, Mahoney JP, Rodrigues JPGLM, Mildorf TJ, Dror RO, Shaw DE, Bouvier M, Pardon E, Steyaert J, Sunahara RK, Weis WI, Zhang C, Kobilka BK. Structural insights into binding specificity, efficacy and bias of a beta2AR partial agonist. Nat Chem Biol. 2018 Nov;14(11):1059-1066. doi: 10.1038/s41589-018-0145-x. Epub, 2018 Oct 16. PMID:30327561 doi:http://dx.doi.org/10.1038/s41589-018-0145-x

Contents


PDB ID 6mxt

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