1uz9
From Proteopedia
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|PDB= 1uz9 |SIZE=350|CAPTION= <scene name='initialview01'>1uz9</scene>, resolution 1.6Å | |PDB= 1uz9 |SIZE=350|CAPTION= <scene name='initialview01'>1uz9</scene>, resolution 1.6Å | ||
|SITE= <scene name='pdbsite=AC1:Cl+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Cl+Binding+Site+For+Chain+B'>AC1</scene> | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CRS:M-CRESOL'>CRS</scene>, <scene name='pdbligand=UZ9:(2S)-2-AMINO-6-({(4R)-4-[(10R,13S)-10,13-DIMETHYL-3-OXOHEXADECAHYDRO-1H-CYCLOPENTA[A]PHENANTHREN-17-YL]PENTANOYL}AMINO)HEXANOIC+ACID'>UZ9</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1uz9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uz9 OCA], [http://www.ebi.ac.uk/pdbsum/1uz9 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1uz9 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
The addition of specific bulky hydrophobic groups to the insulin molecule provides it with affinity for circulating serum albumin and enables it to form soluble macromolecular complexes at the site of subcutaneous injection, thereby securing slow absorption of the insulin analogue into the blood stream and prolonging its half-life once there. N-Lithocholic acid acylated insulin [Lys(B29)-lithocholyl des-(B30) human insulin] has been crystallized and the structure determined by X-ray crystallography at 1.6 A resolution to explore the molecular basis of its assembly. The unit cell in the crystal consists of an insulin hexamer containing two zinc ions, with two m-cresol molecules bound at each dimer-dimer interface stabilizing an R(6) conformation. Six covalently bound lithocholyl groups are arranged symmetrically around the outside of the hexamer. These form specific van der Waals and hydrogen-bonding interactions at the interfaces between neighboring hexamers, possibly representing the kinds of interactions which occur in the soluble aggregates at the site of injection. Comparison with an equivalent nonderivatized native insulin hexamer shows that the addition of the lithocholyl group disrupts neither the important conformational features of the insulin molecule nor its hexamer-forming ability. Indeed, binding studies show that the affinity of N-lithocholyl insulin for the human insulin receptor is not significantly diminished. | The addition of specific bulky hydrophobic groups to the insulin molecule provides it with affinity for circulating serum albumin and enables it to form soluble macromolecular complexes at the site of subcutaneous injection, thereby securing slow absorption of the insulin analogue into the blood stream and prolonging its half-life once there. N-Lithocholic acid acylated insulin [Lys(B29)-lithocholyl des-(B30) human insulin] has been crystallized and the structure determined by X-ray crystallography at 1.6 A resolution to explore the molecular basis of its assembly. The unit cell in the crystal consists of an insulin hexamer containing two zinc ions, with two m-cresol molecules bound at each dimer-dimer interface stabilizing an R(6) conformation. Six covalently bound lithocholyl groups are arranged symmetrically around the outside of the hexamer. These form specific van der Waals and hydrogen-bonding interactions at the interfaces between neighboring hexamers, possibly representing the kinds of interactions which occur in the soluble aggregates at the site of injection. Comparison with an equivalent nonderivatized native insulin hexamer shows that the addition of the lithocholyl group disrupts neither the important conformational features of the insulin molecule nor its hexamer-forming ability. Indeed, binding studies show that the affinity of N-lithocholyl insulin for the human insulin receptor is not significantly diminished. | ||
| - | |||
| - | ==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== | ==About this Structure== | ||
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[[Category: Whittingham, J L.]] | [[Category: Whittingham, J L.]] | ||
[[Category: Wilkinson, A J.]] | [[Category: Wilkinson, A J.]] | ||
| - | [[Category: CL]] | ||
| - | [[Category: CRS]] | ||
| - | [[Category: UZ9]] | ||
| - | [[Category: ZN]] | ||
[[Category: diabetes mellitus]] | [[Category: diabetes mellitus]] | ||
| - | [[Category: hormone disease mutation]] | + | [[Category: hormone disease mutation,]] |
[[Category: insulin]] | [[Category: insulin]] | ||
[[Category: insulin family]] | [[Category: insulin family]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:17:29 2008'' |
Revision as of 21:17, 30 March 2008
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| , resolution 1.6Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , , | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTALLOGRAPHIC AND SOLUTION STUDIES OF N-LITHOCHOLYL INSULIN: A NEW GENERATION OF PROLONGED-ACTING INSULINS.
Overview
The addition of specific bulky hydrophobic groups to the insulin molecule provides it with affinity for circulating serum albumin and enables it to form soluble macromolecular complexes at the site of subcutaneous injection, thereby securing slow absorption of the insulin analogue into the blood stream and prolonging its half-life once there. N-Lithocholic acid acylated insulin [Lys(B29)-lithocholyl des-(B30) human insulin] has been crystallized and the structure determined by X-ray crystallography at 1.6 A resolution to explore the molecular basis of its assembly. The unit cell in the crystal consists of an insulin hexamer containing two zinc ions, with two m-cresol molecules bound at each dimer-dimer interface stabilizing an R(6) conformation. Six covalently bound lithocholyl groups are arranged symmetrically around the outside of the hexamer. These form specific van der Waals and hydrogen-bonding interactions at the interfaces between neighboring hexamers, possibly representing the kinds of interactions which occur in the soluble aggregates at the site of injection. Comparison with an equivalent nonderivatized native insulin hexamer shows that the addition of the lithocholyl group disrupts neither the important conformational features of the insulin molecule nor its hexamer-forming ability. Indeed, binding studies show that the affinity of N-lithocholyl insulin for the human insulin receptor is not significantly diminished.
About this Structure
1UZ9 is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.
Reference
Crystallographic and solution studies of N-lithocholyl insulin: a new generation of prolonged-acting human insulins., Whittingham JL, Jonassen I, Havelund S, Roberts SM, Dodson EJ, Verma CS, Wilkinson AJ, Dodson GG, Biochemistry. 2004 May 25;43(20):5987-95. PMID:15147182
Page seeded by OCA on Mon Mar 31 00:17:29 2008
