Reference : Identification Of Key Residues For Interaction Of Vasoactive Intestinal Peptide With Hum...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/63665
Identification Of Key Residues For Interaction Of Vasoactive Intestinal Peptide With Human Vpac(1) And Vpac(2) Receptors And Development Of A Highly Selective Vpac(1) Receptor Agonist - Alanine Scanning And Molecular Modeling Of The Peptide
English
Nicole, P. [> > > >]
Lins, Laurence mailto [Université de Liège > > Gembloux Agro-Bio Tech >]
Rouyer-Fessard, C. [> > > >]
Drouot, C. [> > > >]
Fulcrand, P. [> > > >]
Thomas, Annick [Université de Liège - ULg > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie moléc. et numér. >]
Couvineau, A. [> > > >]
Martinez, J. [> > > >]
Brasseur, Robert mailto [Université de Liège > > Gembloux Agro-Bio Tech >]
Laburthe, M. [> > > >]
2000
Journal of Biological Chemistry
275
31
24003-12
Yes (verified by ORBi)
International
0021-9258
[en] The widespread neuropeptide vasoactive intestinal peptide (VIP) has two receptors
VPAC(1) and VPAC(2). Solid-phase syntheses of VIP analogs in which each amino
acid has been changed to alanine (Ala scan) or glycine was achieved and each
analog was tested for: (i) three-dimensional structure by ab initio molecular
modeling; (ii) ability to inhibit (125)I-VIP binding (K(i)) and to stimulate
adenylyl cyclase activity (EC(50)) in membranes from cell clones stably
expressing human recombinant VPAC(1) or VPAC(2) receptor. The data show that
substituting residues at 14 positions out of 28 in VIP resulted in a >10-fold
increase of K(i) or EC(50) at the VPAC(1) receptor. Modeling of the
three-dimensional structure of native VIP (central alpha-helice from Val(5) to
Asn(24) with random coiled N and C terminus) and analogs shows that substitutions
of His(1), Val(5), Arg(14), Lys(15), Lys(21), Leu(23), and Ile(26) decreased
biological activity without altering the predicted structure, supporting that
those residues directly interact with VPAC(1) receptor. The interaction of the
analogs with human VPAC(2) receptor is similar to that observed with VPAC(1)
receptor, with three remarkable exceptions: substitution of Thr(11) and Asn(28)
by alanine increased K(i) for binding to VPAC(2) receptor; substitution of
Tyr(22) by alanine increased EC(50) for stimulating adenylyl cyclase activity
through interaction with the VPAC(2) receptor. By combining 3 mutations at
positions 11, 22, and 28, we developed the [Ala(11,22,28)]VIP analog which
constitutes the first highly selective (>1,000-fold) human VPAC(1) receptor
agonist derived from VIP ever described.
Researchers ; Professionals
http://hdl.handle.net/2268/63665

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Restricted access
185-cv.pdfPublisher postprint609.48 kBRequest copy

Bookmark and Share SFX Query

All documents in ORBi are protected by a user license.