2uzi
From Proteopedia
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|PDB= 2uzi |SIZE=350|CAPTION= <scene name='initialview01'>2uzi</scene>, resolution 2.00Å | |PDB= 2uzi |SIZE=350|CAPTION= <scene name='initialview01'>2uzi</scene>, resolution 2.00Å | ||
|SITE= <scene name='pdbsite=AC1:Zn+Binding+Site+For+Chain+R'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Zn+Binding+Site+For+Chain+R'>AC1</scene> | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=GTP:GUANOSINE-5'-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=2uzi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uzi OCA], [http://www.ebi.ac.uk/pdbsum/2uzi PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2uzi RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Many disease-related processes occur via protein complexes that are considered undruggable with small molecules. An example is RAS, which is frequently mutated in cancer and contributes to initiation and maintenance of the disease by constitutive signal transduction through protein interaction with effector proteins, like PI3K, RAF and RALGDS. Such protein interactions are therefore significant targets for therapy. We describe a single immunoglobulin variable region domain that specifically binds to activated GTP-bound RAS and prevents RAS-dependent tumorigenesis in a mouse model. The crystal structure of the immunoglobulin-RAS complex shows that the variable region competitively binds to the conformationally variant regions of RAS, where its signalling effector molecules interact. This allows the plasma membrane targeted single domain intrabody to inhibit signalling by mutant RAS. This mode of action is a novel advance to directly interfere with oncogenic RAS function in human cancer and shows a universally applicable approach to develop macromolecules to combat cancer. In addition, this method illustrates a general means for interfering with protein interactions that are commonly considered intractable as conventional drug targets. | Many disease-related processes occur via protein complexes that are considered undruggable with small molecules. An example is RAS, which is frequently mutated in cancer and contributes to initiation and maintenance of the disease by constitutive signal transduction through protein interaction with effector proteins, like PI3K, RAF and RALGDS. Such protein interactions are therefore significant targets for therapy. We describe a single immunoglobulin variable region domain that specifically binds to activated GTP-bound RAS and prevents RAS-dependent tumorigenesis in a mouse model. The crystal structure of the immunoglobulin-RAS complex shows that the variable region competitively binds to the conformationally variant regions of RAS, where its signalling effector molecules interact. This allows the plasma membrane targeted single domain intrabody to inhibit signalling by mutant RAS. This mode of action is a novel advance to directly interfere with oncogenic RAS function in human cancer and shows a universally applicable approach to develop macromolecules to combat cancer. In addition, this method illustrates a general means for interfering with protein interactions that are commonly considered intractable as conventional drug targets. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Bladder cancer, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190020 190020]], Costello syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190020 190020]], Thyroid carcinoma, follicular, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190020 190020]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Tanaka, T.]] | [[Category: Tanaka, T.]] | ||
[[Category: Williams, R L.]] | [[Category: Williams, R L.]] | ||
| - | [[Category: GTP]] | ||
| - | [[Category: MG]] | ||
| - | [[Category: ZN]] | ||
[[Category: antibody]] | [[Category: antibody]] | ||
[[Category: cancer therapy]] | [[Category: cancer therapy]] | ||
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[[Category: signaling protein/immune system]] | [[Category: signaling protein/immune system]] | ||
| - | ''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 05:06:40 2008'' |
Revision as of 02:06, 31 March 2008
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| , resolution 2.00Å | |||||||
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| Sites: | |||||||
| Ligands: | , , | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF HRAS(G12V)- ANTI-RAS FV COMPLEX
Overview
Many disease-related processes occur via protein complexes that are considered undruggable with small molecules. An example is RAS, which is frequently mutated in cancer and contributes to initiation and maintenance of the disease by constitutive signal transduction through protein interaction with effector proteins, like PI3K, RAF and RALGDS. Such protein interactions are therefore significant targets for therapy. We describe a single immunoglobulin variable region domain that specifically binds to activated GTP-bound RAS and prevents RAS-dependent tumorigenesis in a mouse model. The crystal structure of the immunoglobulin-RAS complex shows that the variable region competitively binds to the conformationally variant regions of RAS, where its signalling effector molecules interact. This allows the plasma membrane targeted single domain intrabody to inhibit signalling by mutant RAS. This mode of action is a novel advance to directly interfere with oncogenic RAS function in human cancer and shows a universally applicable approach to develop macromolecules to combat cancer. In addition, this method illustrates a general means for interfering with protein interactions that are commonly considered intractable as conventional drug targets.
About this Structure
2UZI is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RAS., Tanaka T, Williams RL, Rabbitts TH, EMBO J. 2007 Jul 11;26(13):3250-9. Epub 2007 Jun 14. PMID:17568777
Page seeded by OCA on Mon Mar 31 05:06:40 2008
Categories: Homo sapiens | Protein complex | Rabbitts, T H. | Tanaka, T. | Williams, R L. | Antibody | Cancer therapy | Disease mutation | Golgi apparatus | Gtp-binding | Immunoglobulin domain | Intrabody | Lipoprotein | Membrane | Methylation | Nucleotide-binding | Oncogene | Palmitate | Prenylation | Proto-oncogene | Signal transduction | Signaling protein/immune system
