2hz9: Difference between revisions
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
==Overview== | ==Overview== | ||
The beta-trefoil protein human fibroblast growth factor-1 (FGF-1) is made, up of a six-stranded antiparallel beta-barrel closed off on one end by, three beta-hairpins, thus exhibiting a 3-fold axis of structural symmetry., The N and C terminus beta-strands hydrogen bond to each other and their, interaction is postulated from both NMR and X-ray structure data to be, important in folding and stability. Specific mutations within the adjacent, N and C terminus beta-strands of FGF-1 are shown to provide a substantial, increase in stability. This increase is largely correlated with an, increased folding rate constant, and with a smaller but significant, decrease in the unfolding rate constant. A series of stabilizing mutations, are subsequently combined and result in a doubling of the DeltaG value of, unfolding. When taken in the context of previous studies of stabilizing, mutations, the results indicate that although FGF-1 is known for generally, poor thermal stability, the beta-trefoil architecture appears capable of, substantial thermal stability. Targeting stabilizing mutations within the, N and C terminus beta-strand interactions of a beta-barrel architecture, may be a generally useful approach to increase protein stability. Such, stabilized mutations of FGF-1 are shown to exhibit significant increases, in effective mitogenic potency, and may prove useful as "second, generation" forms of FGF-1 for application in angiogenic therapy. | The beta-trefoil protein human fibroblast growth factor-1 (FGF-1) is made, up of a six-stranded antiparallel beta-barrel closed off on one end by, three beta-hairpins, thus exhibiting a 3-fold axis of structural symmetry., The N and C terminus beta-strands hydrogen bond to each other and their, interaction is postulated from both NMR and X-ray structure data to be, important in folding and stability. Specific mutations within the adjacent, N and C terminus beta-strands of FGF-1 are shown to provide a substantial, increase in stability. This increase is largely correlated with an, increased folding rate constant, and with a smaller but significant, decrease in the unfolding rate constant. A series of stabilizing mutations, are subsequently combined and result in a doubling of the DeltaG value of, unfolding. When taken in the context of previous studies of stabilizing, mutations, the results indicate that although FGF-1 is known for generally, poor thermal stability, the beta-trefoil architecture appears capable of, substantial thermal stability. Targeting stabilizing mutations within the, N and C terminus beta-strand interactions of a beta-barrel architecture, may be a generally useful approach to increase protein stability. Such, stabilized mutations of FGF-1 are shown to exhibit significant increases, in effective mitogenic potency, and may prove useful as "second, generation" forms of FGF-1 for application in angiogenic therapy. | ||
==Disease== | |||
Known diseases associated with this structure: Aplasia of lacrimal and salivary glands OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602115 602115]], LADD syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602115 602115]] | |||
==About this Structure== | ==About this Structure== | ||
2HZ9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=FMT:'>FMT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HZ9 OCA]. | 2HZ9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=FMT:'>FMT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Sites: <scene name='pdbsite=AC1:So4+Binding+Site+For+Residue+A+141'>AC1</scene>, <scene name='pdbsite=AC2:Fmt+Binding+Site+For+Residue+B+141'>AC2</scene>, <scene name='pdbsite=AC3:Fmt+Binding+Site+For+Residue+A+142'>AC3</scene>, <scene name='pdbsite=AC4:Fmt+Binding+Site+For+Residue+B+142'>AC4</scene> and <scene name='pdbsite=AC5:Fmt+Binding+Site+For+Residue+B+143'>AC5</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HZ9 OCA]. | ||
==Reference== | ==Reference== | ||
| Line 20: | Line 23: | ||
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: beta-trefoil]] | [[Category: beta-trefoil]] | ||
[[Category: hormone/growth factor complex]] | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:17:31 2008'' | ||
Revision as of 09:17, 13 February 2008
|
Crystal structure of Lys12Val/Asn95Val/Cys117Val mutant of human acidic fibroblast growth factor at 1.70 angstrom resolution.
OverviewOverview
The beta-trefoil protein human fibroblast growth factor-1 (FGF-1) is made, up of a six-stranded antiparallel beta-barrel closed off on one end by, three beta-hairpins, thus exhibiting a 3-fold axis of structural symmetry., The N and C terminus beta-strands hydrogen bond to each other and their, interaction is postulated from both NMR and X-ray structure data to be, important in folding and stability. Specific mutations within the adjacent, N and C terminus beta-strands of FGF-1 are shown to provide a substantial, increase in stability. This increase is largely correlated with an, increased folding rate constant, and with a smaller but significant, decrease in the unfolding rate constant. A series of stabilizing mutations, are subsequently combined and result in a doubling of the DeltaG value of, unfolding. When taken in the context of previous studies of stabilizing, mutations, the results indicate that although FGF-1 is known for generally, poor thermal stability, the beta-trefoil architecture appears capable of, substantial thermal stability. Targeting stabilizing mutations within the, N and C terminus beta-strand interactions of a beta-barrel architecture, may be a generally useful approach to increase protein stability. Such, stabilized mutations of FGF-1 are shown to exhibit significant increases, in effective mitogenic potency, and may prove useful as "second, generation" forms of FGF-1 for application in angiogenic therapy.
DiseaseDisease
Known diseases associated with this structure: Aplasia of lacrimal and salivary glands OMIM:[602115], LADD syndrome OMIM:[602115]
About this StructureAbout this Structure
2HZ9 is a Single protein structure of sequence from Homo sapiens with and as ligands. Known structural/functional Sites: , , , and . Full crystallographic information is available from OCA.
ReferenceReference
Spackling the Crack: Stabilizing Human Fibroblast Growth Factor-1 by Targeting the N and C terminus beta-Strand Interactions., Dubey VK, Lee J, Somasundaram T, Blaber S, Blaber M, J Mol Biol. 2007 Aug 3;371(1):256-68. Epub 2007 May 31. PMID:17570396
Page seeded by OCA on Wed Feb 13 08:17:31 2008