The Forgotten Serine

Previous work in the β2-adrenergic receptor demonstrated critical interactions between Ser-204 and Ser-207 in the fifth membrane-spanning segment and the meta-OH and para-OH, respectively, of catecholamine agonists (Strader, C. D., Candelore, M. R., Hill, W. S., Sigal, I. S., and Dixon, R. A. (1989) J. Biol. Chem. 264, 13572–13578). Using the substituted cysteine accessibility method in the β2-adrenergic receptor, we have found that in addition to Ser-204 and Ser-207, Ser-203 is also accessible on the surface of the binding-site crevice and is occluded by bound agonist. Mutation of Ser-203 to Ala, Val, or Cys reduced the binding affinity and adenylyl cyclase-activating potency of agonists containing ameta-OH, whereas their affinities and potencies were largely preserved by mutation of Ser-203 to Thr, which maintained an OH at this position. Thus both Ser-203 and Ser-204 appear to interact with the meta-OH of catecholamines, perhaps through a bifurcated H bond. Furthermore, the removal of the OH at position 203 led to a significant loss of affinity of antagonists with nitrogen in their heterocyclic ring structure. The greatest effect was seen with pindolol, a partial agonist, suggesting that a H bond between the heterocyclic ring and Ser-203 may play a role in partial agonism. In contrast, the affinities of antagonists such as propranolol or alprenolol, which have cyclic structures without H-bonding capability, were unaltered after mutation of Ser-203.

• Publication year

  2000

• Venue

  Journal of Biological Chemistry

• Publication date

  2000-12-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/JBC.M002092200PMID 10964911
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Loss of the OH at position 203 reduces affinity of antagonists with heterocyclic ring structure, with the largest effect on pindolol, consistent with a role for a Ser-203 hydrogen bond in partial agonism.

  Confidence 0.96

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• Ser-203 and Ser-204 both appear to contact the meta-OH of catecholamines, possibly through a bifurcated hydrogen bond.

  Confidence 0.95

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• Replacing Ser-203 with Ala, Val, or Cys lowers the affinity and adenylyl cyclase-activating potency of catecholamine agonists with a meta-OH group, whereas Ser-203Thr largely preserves both.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• Ser-203 is accessible on the surface of the β2-adrenergic receptor binding-site crevice and becomes occluded when agonist is bound.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review

• antagonists with heterocyclic ring structure

  ligand class

  Antagonist ligands containing heterocyclic ring systems that were examined for altered binding after Ser-203 mutation.

  Aliases: heterocyclic antagonists

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• catecholamine agonists

  ligand class

  Agonist ligands with catechol hydroxyl substitutions that were tested for binding and signaling at the receptor.

  Aliases: catecholamines

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• pindolol

  small molecule

  A partial-agonist antagonist ligand used as a probe of Ser-203-dependent binding effects.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• ser-203

  amino acid residue

  A serine residue in transmembrane segment 5 of the β2-adrenergic receptor that was mutated and probed for ligand contacts.

  Aliases: S203, Ser203

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• ser-204

  amino acid residue

  A neighboring serine residue in transmembrane segment 5 of the β2-adrenergic receptor previously implicated in catecholamine binding.

  Aliases: S204, Ser204

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• ser-207

  amino acid residue

  A serine residue in transmembrane segment 5 of the β2-adrenergic receptor previously implicated in catecholamine binding.

  Aliases: S207, Ser207

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• substituted cysteine accessibility method

  experimental method

  A cysteine-scanning accessibility assay used to test whether receptor positions are exposed in the binding-site crevice.

  Aliases: SCAM

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review
• β2-adrenergic receptor

  receptor

  A G protein-coupled receptor used here as the protein target for mapping ligand-contacting residues.

  Aliases: beta2-adrenergic receptor, β2AR

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewKiller Whale (322360f1c1) reviewmexicorea (qjvnbu8xg3) review

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