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3-D pictures of a cancer-promoting enzyme

Researchers at Johns Hopkins have built a 3-D picture of an enzyme which can promote many types of cancers after mutation. This enzyme, known as PIK3CA, "is mutated frequently in many cancers, including colon, brain, stomach, breast and lung." According to the researchers, the new details discovered about the enzyme structure could help scientists design new drugs to fight these cancers. Already, there is a clinical trial of a broad-spectrum drug that targets all PI3K family members. But the scientists hope that new trials will begin soon to evaluate drugs focused on PI3Kα, the only form that is mutated in cancers. But read more...
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Written by Roland Piquepaille, Inactive on

Researchers at Johns Hopkins have built a 3-D picture of an enzyme which can promote many types of cancers after mutation. This enzyme, known as PIK3CA, "is mutated frequently in many cancers, including colon, brain, stomach, breast and lung." According to the researchers, the new details discovered about the enzyme structure could help scientists design new drugs to fight these cancers. Already, there is a clinical trial of a broad-spectrum drug that targets all PI3K family members. But the scientists hope that new trials will begin soon to evaluate drugs focused on PI3Kα, the only form that is mutated in cancers. But read more...

Images of the PI3K enzyme

You can see on the left "the structure of class IA human PI3K, an enzyme complex that is frequently mutated in human cancers." The images show the "intermolecular contact in the p110α/p85 heterodimer crystal: (A) Ribbon diagram of a p110α/niSH2 heterodimer and a neighboring molecule; (B) Molecular surface of the PI3K colored as electrostatic charges showing the Ras binding domain of a neighboring molecule (green ribbon with blue back-side)." (Credit: Johns Hopkins University School of Medicine and Howard Hughes Medical Institute) And by the way, according to Cancer GeneticsWeb, PIK3CA is an abbreviation for "Phosphatidylinositol 3-kinase, catalytic, alpha polypeptide."

Now, let's listen to what the researchers have to say. "'We tried to guess how the enzyme's activity was affected by the mutations based on their locations along the length of the protein,' says L. Mario Amzel, Ph.D., professor and director of biophysics and biophysical chemistry at Hopkins. 'But without a 3-D structure, it's hard to do. It's like having a puzzle but missing critical pieces.' The research team isolated purified PIK3CA and part of another protein it normally binds to, grew crystals of the purified enzyme bound to its partner and figured out its 3-D structure using techniques that shoot X-rays through the protein crystals. Using computers, they analyzed the X-ray pattern and assembled a 3-D model of the enzyme. Onto this model the researchers then mapped all the cancer-associated mutations."

And according to Sandra Gabelli, [a member of the Amzel Lab, and] an instructor of biophysics and biophysical chemistry at Hopkins, the researchers originally suspected that the mutations somehow interfered with the way PIK3CA interacted with other proteins and parts of the cell and therefore must be on the outside surface of the enzyme. However, their results show that nearly all the mutations map to regions within the enzyme.

In a previous news release, "Enzyme Structure Reveals New Targets for Cancer Drugs," the Howard Hughes Medical Institute (HMMI), gave additional details. "'Structures always have some intrinsic beauty and interest on their own, but the reason we're particularly interested in this protein is because the gene that encodes it is very commonly mutated in human cancers,' said Bert Vogelstein, a Howard Hughes Medical Institute investigator at the Kimmel Cancer Center at Johns Hopkins University School of Medicine. 'Heretofore, only one structure has been reported in this family of enzymes and it is quite different. The new data show what these differences are and, hopefully, will speed up drug development.'"

Vogelstein added that "tThat new knowledge is critical as new classes of cancer-inhibiting drugs are being developed to target mutated forms of the enzyme. The first clinical trial of a broad-spectrum drug that targets all PI3K family members is underway, he said, but the hope is that new trials will soon be initiated to evaluate drugs that zero in on PI3K alpha, the only form that is mutated in cancers."

For more information, this research work has been published in Science under the more or less enigmatic title "The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations" (Volume 318, Number 5857, Pages 1744-1748, December 14, 2007). Here are two links to the abstract of this research paper and to some supporting online material (PDF format, 9 pages, 5.18 MB). The above images have been extracted from this last document.

Sources: Johns Hopkins Medical Institutions news release, January 4, 2008; Howard Hughes Medical Institute (HMMI) news release, December 17, 2007; and various websites

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