View source for 2juu

[[Image:2juu.gif|left|200px]]<br /><applet load="2juu" size="350" color="white" frame="true" align="right" spinBox="true" 
caption="2juu" />
'''allo-ThrA3 DKP-insulin'''<br />

==Overview==
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.

==Disease==
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], Hyperproinsulinemia, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], MODY, one form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]]

==About this Structure==
2JUU is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JUU 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17884811 17884811]
[[Category: Protein complex]]
[[Category: Chan, S.]]
[[Category: Chu, Y.]]
[[Category: Hua, Q.]]
[[Category: Huang, K.]]
[[Category: Jia, W.]]
[[Category: Katsoyannis, P G.]]
[[Category: Klaproth, B.]]
[[Category: Meyts, P De.]]
[[Category: Nakagawa, S H.]]
[[Category: Steiner, D F.]]
[[Category: Wang, R.]]
[[Category: Weiss, M A.]]
[[Category: Whittaker, J.]]
[[Category: allo-thra3]]
[[Category: carbohydrate metabolism]]
[[Category: cleavage on pair of basic residues]]
[[Category: diabetes mellitus]]
[[Category: disease mutation]]
[[Category: glucose metabolism]]
[[Category: hormone]]
[[Category: insulin]]
[[Category: nmr]]
[[Category: pharmaceutical]]
[[Category: secreted]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:06:01 2008''