2juv

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[[Image:2juv.gif|left|200px]]
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{{Seed}}
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{{STRUCTURE_2juv| PDB=2juv | SCENE= }}
{{STRUCTURE_2juv| PDB=2juv | SCENE= }}
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'''AbaA3-DKP-insulin'''
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===AbaA3-DKP-insulin===
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==Overview==
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The contribution of the insulin A-chain to receptor binding is investigated by photo-cross-linking and nonstandard mutagenesis. Studies focus on the role of Val(A3), which projects within a crevice between the A- and B-chains. Engineered receptor alpha-subunits containing specific protease sites ("midi-receptors") are employed to map the site of photo-cross-linking by an analog containing a photoactivable A3 side chain (para-azido-Phe (Pap)). The probe cross-links to a C-terminal peptide (residues 703-719 of the receptor A isoform, KTFEDYLHNVVFVPRPS) containing side chains critical for hormone binding (underlined); the corresponding segment of the holoreceptor was shown previously to cross-link to a Pap(B25)-insulin analog. Because Pap is larger than Val and so may protrude beyond the A3-associated crevice, we investigated analogs containing A3 substitutions comparable in size to Val as follows: Thr, allo-Thr, and alpha-aminobutyric acid (Aba). Substitutions were introduced within an engineered monomer. Whereas previous studies of smaller substitutions (Gly(A3) and Ser(A3)) encountered nonlocal conformational perturbations, NMR structures of the present analogs are similar to wild-type insulin; the variant side chains are accommodated within a native-like crevice with minimal distortion. Receptor binding activities of Aba(A3) and allo-Thr(A3) analogs are reduced at least 10-fold; the activity of Thr(A3)-DKP-insulin is reduced 5-fold. The hormone-receptor interface is presumably destabilized either by a packing defect (Aba(A3)) or by altered polarity (allo-Thr(A3) and Thr(A3)). Our results provide evidence that Val(A3), a site of mutation causing diabetes mellitus, contacts the insert domain-derived tail of the alpha-subunit in a hormone-receptor complex.
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(as it appears on PubMed at http://www.pubmed.gov), where 17884811 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17884811}}
==About this Structure==
==About this Structure==
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2JUV is a [[Protein complex]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JUV OCA].
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2JUV is a [[Protein complex]] structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JUV OCA].
==Reference==
==Reference==
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[[Category: Pharmaceutical]]
[[Category: Pharmaceutical]]
[[Category: Secreted]]
[[Category: Secreted]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:18:48 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 11:16:52 2008''

Revision as of 08:16, 29 July 2008

Image:2juv.png

Template:STRUCTURE 2juv

AbaA3-DKP-insulin

Template:ABSTRACT PUBMED 17884811

About this Structure

2JUV is a Protein complex structure. Full experimental information is available from OCA.

Reference

The A-chain of insulin contacts the insert domain of the insulin receptor. Photo-cross-linking and mutagenesis of a diabetes-related crevice., Huang K, Chan SJ, Hua QX, Chu YC, Wang RY, Klaproth B, Jia W, Whittaker J, De Meyts P, Nakagawa SH, Steiner DF, Katsoyannis PG, Weiss MA, J Biol Chem. 2007 Nov 30;282(48):35337-49. Epub 2007 Sep 20. PMID:17884811

Page seeded by OCA on Tue Jul 29 11:16:52 2008

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