2UZI

Crystal structure of HRAS(G12V) - anti-RAS Fv complex

Summary for 2UZI

• Entry DOI: 10.2210/pdb2uzi/pdb
• Related: 121P 1AA9 1AGP 1BKD 1CLU 1CRP 1CRQ 1CRR 1CTQ 1GNP 1GNQ 1GNR 1HE8 1IAQ 1IOZ 1JAH 1JAI 1K8R 1LF0 1LF5 1LFD 1NVU 1NVV 1NVW 1NVX 1P2S 1P2T 1P2U 1P2V 1PLJ 1PLK 1PLL 1Q21 1QRA 1RVD 1WQ1 1XCM 1XD2 1XJ0 1ZVQ 1ZW6 221P 2C5L 2CE2 2CL0 2CL6 2CL7 2CLC 2CLD 2EVW 2GDP 2Q21 421P 4Q21 521P 5P21 621P 6Q21 721P 821P
• Descriptor: ANTI-RAS FV HEAVY CHAIN, ANTI-RAS FV LIGHT CHAIN, GTPASE HRAS, ... (7 entities in total)
• Functional Keywords: signal transduction, immunoglobulin domain, membrane, antibody, oncogene, palmitate, intrabody, disease mutation, nucleotide-binding, proto-oncogene, cancer therapy, golgi apparatus, prenylation, methylation, lipoprotein, gtp- binding, signaling protein/immune system, signaling protein-immune system complex
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cell membrane. Isoform 2: Nucleus: P01112
• Total number of polymer chains: 3
• Total formula weight: 43700.55

Authors

Tanaka, T.,williams, R.L.,Rabbitts, T.H. (deposition date: 2007-04-27, release date: 2007-06-26, Last modification date: 2024-11-13)

Primary citation

Tanaka, T.,Williams, R.L.,Rabbitts, T.H.
Tumour Prevention by a Single Antibody Domain Targeting the Interaction of Signal Transduction Proteins with Ras.
Embo J., 26:3250-, 2007

PubMed Abstract: 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.

PubMed: 17568777
DOI: 10.1038/SJ.EMBOJ.7601744

Experimental method

X-RAY DIFFRACTION (2 Å)