The mid-region of parathyroid hormone (1-34) serves as a functional docking domain in receptor activation
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- A Wittelsberger
- M Corich
- BE Thomas
- BK Lee
- A Barazza
- P Czodrowski
- DF Mierke
- M Chorev
- M Rosenblatt
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000235451600005&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/bi051833a
- Externe Identifier
- Clarivate Analytics Document Solution ID: 014AR
- PubMed Identifier: 16475791
- ISSN
- 0006-2960
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- BIOCHEMISTRY
- Paginierung
- 2027 - 2034
- Datum der Veröffentlichung
- 2006
- Status
- Published
- Titel
- The mid-region of parathyroid hormone (1-34) serves as a functional docking domain in receptor activation
- Sub types
- Article
- Ausgabe der Zeitschrift
- 45
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Angela Wittelsberger
- Martina Corich
- Beena E Thomas
- Byung-Kwon Lee
- Alessandra Barazza
- Paul Czodrowski
- Dale F Mierke
- Michael Chorev
- Michael Rosenblatt
- DOI
- 10.1021/bi051833a
- eISSN
- 1520-4995
- ISSN
- 0006-2960
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Biochemistry
- Sprache
- en
- Online publication date
- 2006
- Paginierung
- 2027 - 2034
- Datum der Veröffentlichung
- 2006
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/bi051833a
- Datum der Datenerfassung
- 2023
- Titel
- The Mid-Region of Parathyroid Hormone (1−34) Serves as a Functional Docking Domain in Receptor Activation
- Ausgabe der Zeitschrift
- 45
Data source: Crossref
- Abstract
- Elucidating the bimolecular interface between parathyroid hormone (PTH) and its cognate G protein-coupled receptor (PTHR1) should yield insights into the basis of molecular recognition and the mechanism of ligand-mediated intracellular signaling for a system that is critically important in regulating calcium levels in blood. We used photoaffinity scanning (PAS) to identify key ligand-receptor interactions for residues from the unstructured mid-region domain of PTH-(1-34). Four PTH analogues, containing a single photoreactive p-benzoylphenylalanine (Bpa) residue in position 11, 15, 18, or 21, were found to photo-cross-link within receptor regions [165-176], [183-189], [190-298], and [165-176], respectively. Addition of these mid-region contacts as constraints to our previously proposed model of the PTH-PTHR1 complex and extensive molecular simulation experiments enables substantial refinement of the model. Specifically, (1) the overall receptor-bound conformation of the hormone is not extended, but bent; (2) helix [169-176] of the N-terminal extracellular domain (N-ECD) of the receptor is redirected toward the heptahelical bundle; and (3) the hormone traverses between the top of transmembrane (TM) helices 1 and 2, rather than between TM-7 and TM-1. This significantly alters the model of both the receptor-bound tertiary structure of the hormone and the topological orientation of the C-terminus of the N-ECD in the hormone-receptor bimolecular complex. We propose that the mid-region of PTH-(1-34) has a role in fixing, by extensive contacts with the receptor, the entry of the N-terminal helix of the hormone into the heptahelical bundle between TM-1 and TM-2. This anchorage would orient the amino terminus into position to activate the receptor.
- Addresses
- Department of Physiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA. Angela.Wittelsberger@tufts.edu
- Autoren
- Angela Wittelsberger
- Martina Corich
- Beena E Thomas
- Byung-Kwon Lee
- Alessandra Barazza
- Paul Czodrowski
- Dale F Mierke
- Michael Chorev
- Michael Rosenblatt
- DOI
- 10.1021/bi051833a
- eISSN
- 1520-4995
- Externe Identifier
- PubMed Identifier: 16475791
- Funding acknowledgements
- NIDDK NIH HHS: DK-47940
- NIGMS NIH HHS: GM-54082
- Open access
- false
- ISSN
- 0006-2960
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Biochemistry
- Schlüsselwörter
- Cells, Cultured
- COS Cells
- Animals
- Humans
- Parathyroid Hormone
- Peptide Fragments
- Receptors, Parathyroid Hormone
- Receptor, Parathyroid Hormone, Type 1
- Protein Structure, Tertiary
- Models, Molecular
- Chlorocebus aethiops
- Sprache
- eng
- Medium
- Paginierung
- 2027 - 2034
- Datum der Veröffentlichung
- 2006
- Status
- Published
- Datum der Datenerfassung
- 2006
- Titel
- The mid-region of parathyroid hormone (1-34) serves as a functional docking domain in receptor activation.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural
- Ausgabe der Zeitschrift
- 45
Data source: Europe PubMed Central
- Abstract
- Elucidating the bimolecular interface between parathyroid hormone (PTH) and its cognate G protein-coupled receptor (PTHR1) should yield insights into the basis of molecular recognition and the mechanism of ligand-mediated intracellular signaling for a system that is critically important in regulating calcium levels in blood. We used photoaffinity scanning (PAS) to identify key ligand-receptor interactions for residues from the unstructured mid-region domain of PTH-(1-34). Four PTH analogues, containing a single photoreactive p-benzoylphenylalanine (Bpa) residue in position 11, 15, 18, or 21, were found to photo-cross-link within receptor regions [165-176], [183-189], [190-298], and [165-176], respectively. Addition of these mid-region contacts as constraints to our previously proposed model of the PTH-PTHR1 complex and extensive molecular simulation experiments enables substantial refinement of the model. Specifically, (1) the overall receptor-bound conformation of the hormone is not extended, but bent; (2) helix [169-176] of the N-terminal extracellular domain (N-ECD) of the receptor is redirected toward the heptahelical bundle; and (3) the hormone traverses between the top of transmembrane (TM) helices 1 and 2, rather than between TM-7 and TM-1. This significantly alters the model of both the receptor-bound tertiary structure of the hormone and the topological orientation of the C-terminus of the N-ECD in the hormone-receptor bimolecular complex. We propose that the mid-region of PTH-(1-34) has a role in fixing, by extensive contacts with the receptor, the entry of the N-terminal helix of the hormone into the heptahelical bundle between TM-1 and TM-2. This anchorage would orient the amino terminus into position to activate the receptor.
- Autoren
- Angela Wittelsberger
- Martina Corich
- Beena E Thomas
- Byung-Kwon Lee
- Alessandra Barazza
- Paul Czodrowski
- Dale F Mierke
- Michael Chorev
- Michael Rosenblatt
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/16475791
- DOI
- 10.1021/bi051833a
- Funding acknowledgements
- NIDDK NIH HHS: DK-47940
- NIGMS NIH HHS: GM-54082
- ISSN
- 0006-2960
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Biochemistry
- Schlüsselwörter
- Animals
- COS Cells
- Cells, Cultured
- Chlorocebus aethiops
- Humans
- Models, Molecular
- Parathyroid Hormone
- Peptide Fragments
- Protein Structure, Tertiary
- Receptor, Parathyroid Hormone, Type 1
- Receptors, Parathyroid Hormone
- Sprache
- eng
- Country
- United States
- Paginierung
- 2027 - 2034
- Datum der Veröffentlichung
- 2006
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2006
- Titel
- The mid-region of parathyroid hormone (1-34) serves as a functional docking domain in receptor activation.
- Sub types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 45
Data source: PubMed
- Beziehungen:
-