1zeg
From Proteopedia
(New page: 200px<br /> <applet load="1zeg" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zeg, resolution 1.6Å" /> '''STRUCTURE OF B28 ASP...) |
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| - | [[Image:1zeg.gif|left|200px]]<br /> | + | [[Image:1zeg.gif|left|200px]]<br /><applet load="1zeg" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1zeg" size=" | + | |
caption="1zeg, resolution 1.6Å" /> | caption="1zeg, resolution 1.6Å" /> | ||
'''STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL'''<br /> | '''STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Insulin's natural tendency to form dimers and hexamers is significantly | + | Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --> Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and m-cresol. In these crystals, insulin exists as R6 zinc hexamers containing a number of phenol or m-cresol molecules associated with aromatic side chains at the dimer-dimer interfaces. At the monomer-monomer interfaces, the B28 Pro --> Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and A1 Gly, has also determined. This forms an R6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two m-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1ZEG is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, CL and IPH as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1ZEG is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=IPH:'>IPH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZEG OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Antson, A | + | [[Category: Antson, A A.]] |
| - | [[Category: Clarkson, J | + | [[Category: Clarkson, J M.]] |
| - | [[Category: Dodson, G | + | [[Category: Dodson, G G.]] |
| - | [[Category: Edwards, E | + | [[Category: Edwards, E J.]] |
| - | [[Category: Whittingham, J | + | [[Category: Whittingham, J L.]] |
[[Category: CL]] | [[Category: CL]] | ||
[[Category: IPH]] | [[Category: IPH]] | ||
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[[Category: metabolic role]] | [[Category: metabolic role]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:14:45 2008'' |
Revision as of 14:14, 21 February 2008
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STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL
Contents |
Overview
Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --> Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and m-cresol. In these crystals, insulin exists as R6 zinc hexamers containing a number of phenol or m-cresol molecules associated with aromatic side chains at the dimer-dimer interfaces. At the monomer-monomer interfaces, the B28 Pro --> Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and A1 Gly, has also determined. This forms an R6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two m-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions.
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
1ZEG is a Protein complex structure of sequences from Homo sapiens with , and as ligands. Full crystallographic information is available from OCA.
Reference
Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues., Whittingham JL, Edwards DJ, Antson AA, Clarkson JM, Dodson GG, Biochemistry. 1998 Aug 18;37(33):11516-23. PMID:9708987
Page seeded by OCA on Thu Feb 21 16:14:45 2008
Categories: Homo sapiens | Protein complex | Antson, A A. | Clarkson, J M. | Dodson, G G. | Edwards, E J. | Whittingham, J L. | CL | IPH | ZN | Chemical activity | Cross-link | Diabetes | Glucose metabolism | Hormone | Insulin mutant | Metabolic role
