1q4v
From Proteopedia
(New page: 200px<br /> <applet load="1q4v" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q4v, resolution 2.00Å" /> '''CRYSTAL STRUCTURE O...) |
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caption="1q4v, resolution 2.00Å" /> | caption="1q4v, resolution 2.00Å" /> | ||
'''CRYSTAL STRUCTURE OF ALLO-ILEA2-INSULIN, AN INACTIVE CHIRAL ANALOGUE: IMPLICATIONS FOR THE MECHANISM OF RECEPTOR'''<br /> | '''CRYSTAL STRUCTURE OF ALLO-ILEA2-INSULIN, AN INACTIVE CHIRAL ANALOGUE: IMPLICATIONS FOR THE MECHANISM OF RECEPTOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The crystal structure of an inactive chiral analogue of insulin containing | + | The crystal structure of an inactive chiral analogue of insulin containing nonstandard substitution allo-Ile(A2) is described at 2.0 A resolution. In native insulin, the invariant Ile(A2) side chain anchors the N-terminal alpha-helix of the A-chain to the hydrophobic core. The structure of the variant protein was determined by molecular replacement as a T(3)R(3) zinc hexamer. Whereas respective T- and R-state main-chain structures are similar to those of native insulin (main-chain root-mean-square deviations (RMSD) of 0.45 and 0.54 A, respectively), differences in core packing are observed near the variant side chain. The R-state core resembles that of the native R-state with a local inversion of A2 orientation (core side chain RMSD 0.75 A excluding A2); in the T-state, allo-Ile(A2) exhibits an altered conformation in association with the reorganization of the surrounding side chains (RMSD 0.98 A). Surprisingly, the core of the R-state is similar to that observed in solution nuclear magnetic resonance (NMR) studies of an engineered T-like monomer containing the same chiral substitution (allo-Ile(A2)-DKP-insulin; Xu, B., Hua, Q. X., Nakagawa, S. H., Jia, W., Chu, Y. C., Katsoyannis, P. G., and Weiss, M. A. (2002) J. Mol. Biol. 316, 435-441). Simulation of NOESY spectra based on crystallographic protomers enables the analysis of similarities and differences in solution. The different responses of the T- and R-state cores to chiral perturbation illustrates both their intrinsic plasticity and constraints imposed by hexamer assembly. Although variant T- and R-protomers retain nativelike protein surfaces, the receptor-binding activity of allo-Ile(A2)-insulin is low (2% relative to native insulin). This seeming paradox suggests that insulin undergoes a change in conformation to expose Ile(A2) at the hormone-receptor interface. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1Q4V is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with ZN and IPH as [http://en.wikipedia.org/wiki/ligands ligands]. This structure | + | 1Q4V is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=IPH:'>IPH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entries 1PC1 and 1LW8. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q4V OCA]. |
==Reference== | ==Reference== | ||
Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding., Wan ZL, Xu B, Chu YC, Katsoyannis PG, Weiss MA, Biochemistry. 2003 Nov 11;42(44):12770-83. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14596591 14596591] | Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding., Wan ZL, Xu B, Chu YC, Katsoyannis PG, Weiss MA, Biochemistry. 2003 Nov 11;42(44):12770-83. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14596591 14596591] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Chu, Y | + | [[Category: Chu, Y C.]] |
| - | [[Category: Katsoyannis, P | + | [[Category: Katsoyannis, P G.]] |
| - | [[Category: Wan, Z | + | [[Category: Wan, Z L.]] |
| - | [[Category: Weiss, M | + | [[Category: Weiss, M A.]] |
[[Category: Xu, B.]] | [[Category: Xu, B.]] | ||
[[Category: IPH]] | [[Category: IPH]] | ||
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[[Category: protein unfolding]] | [[Category: protein unfolding]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:35:55 2008'' |
Revision as of 12:36, 21 February 2008
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CRYSTAL STRUCTURE OF ALLO-ILEA2-INSULIN, AN INACTIVE CHIRAL ANALOGUE: IMPLICATIONS FOR THE MECHANISM OF RECEPTOR
Contents |
Overview
The crystal structure of an inactive chiral analogue of insulin containing nonstandard substitution allo-Ile(A2) is described at 2.0 A resolution. In native insulin, the invariant Ile(A2) side chain anchors the N-terminal alpha-helix of the A-chain to the hydrophobic core. The structure of the variant protein was determined by molecular replacement as a T(3)R(3) zinc hexamer. Whereas respective T- and R-state main-chain structures are similar to those of native insulin (main-chain root-mean-square deviations (RMSD) of 0.45 and 0.54 A, respectively), differences in core packing are observed near the variant side chain. The R-state core resembles that of the native R-state with a local inversion of A2 orientation (core side chain RMSD 0.75 A excluding A2); in the T-state, allo-Ile(A2) exhibits an altered conformation in association with the reorganization of the surrounding side chains (RMSD 0.98 A). Surprisingly, the core of the R-state is similar to that observed in solution nuclear magnetic resonance (NMR) studies of an engineered T-like monomer containing the same chiral substitution (allo-Ile(A2)-DKP-insulin; Xu, B., Hua, Q. X., Nakagawa, S. H., Jia, W., Chu, Y. C., Katsoyannis, P. G., and Weiss, M. A. (2002) J. Mol. Biol. 316, 435-441). Simulation of NOESY spectra based on crystallographic protomers enables the analysis of similarities and differences in solution. The different responses of the T- and R-state cores to chiral perturbation illustrates both their intrinsic plasticity and constraints imposed by hexamer assembly. Although variant T- and R-protomers retain nativelike protein surfaces, the receptor-binding activity of allo-Ile(A2)-insulin is low (2% relative to native insulin). This seeming paradox suggests that insulin undergoes a change in conformation to expose Ile(A2) at the hormone-receptor interface.
Disease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
About this Structure
1Q4V is a Single protein structure of sequence from [1] with and as ligands. This structure supersedes the now removed PDB entries 1PC1 and 1LW8. Full crystallographic information is available from OCA.
Reference
Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding., Wan ZL, Xu B, Chu YC, Katsoyannis PG, Weiss MA, Biochemistry. 2003 Nov 11;42(44):12770-83. PMID:14596591
Page seeded by OCA on Thu Feb 21 14:35:55 2008
