Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

Advances in protein structure prediction and design

Abstract: The prediction of protein three-dimensional structure from amino acid sequence has been a grand challenge problem in computational biophysics for decades, owing to its intrinsic scientific interest and also to the many potential applications for robust protein structure prediction algorithms, from genome interpretation to protein function prediction. More recently, the inverse problem - designing an amino acid sequence that will fold into a specified three-dimensional structure - has attracted growing attention as a potential route to the rational engineering of proteins with functions useful in biotechnology and medicine. Methods for the prediction and design of protein structures have advanced dramatically in the past decade. Increases in computing power and the rapid growth in protein sequence and structure databases have fuelled the development of new data-intensive and computationally demanding approaches for structure prediction. New algorithms for designing protein folds and protein-protein interfaces have been used to engineer novel high-order assemblies and to design from scratch fluorescent proteins with novel or enhanced properties, as well as signalling proteins with therapeutic potential. In this Review, we describe current approaches for protein structure prediction and design and highlight a selection of the successful applications they have enabled.

Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family

Abstract: NKG2D is an activating receptor that is expressed on most natural killer (NK) cells, CD8 alphabeta T cells, and gammadelta T cells. Among its ligands is the distant major histocompatibility complex class I homolog MICA, which has no function in antigen presentation but is induced by cellular stress. To extend previous functional evidence, the NKG2D-MICA interaction was studied in isolation. NKG2D homodimers formed stable complexes with monomeric MICA in solution, demonstrating that no other components were required to facilitate this interaction. MICA glycosylation was not essential but enhanced complex formation. Soluble NKG2D also bound to cell surface MICB, which has structural and functional properties similar to those of MICA. Moreover, NKG2D stably interacted with surface molecules encoded by three newly identified cDNA sequences (N2DL-1, -2, and -3), which are identical to the human ULBP proteins and may represent homologs of the mouse retinoic acid-early inducible family of NKG2D ligands. Because of the substantial sequence divergence among these molecules, these results indicated promiscuous modes of receptor binding. Comparison of allelic variants of MICA revealed large differences in NKG2D binding that were associated with a single amino acid substitution at position 129 in the alpha2 domain. Varying affinities of MICA alleles for NKG2D may affect thresholds of NK-cell triggering and T-cell modulation.

Polymorphic Repeats in the Androgen Receptor Gene: Molecular Markers of Prostate Cancer Risk

Abstract: We analyzed the polymorphic (CAG)n and (GGN)n regions within the androgen receptor gene from participants in a population-based case-control study of prostate cancer in middle-aged (40-64 years) Caucasian men. The associations between repeat lengths and risk of prostate cancer and the effects of confounding and modifying factors, such as age, family history of prostate cancer, and body mass index, were evaluated. DNA was available for 301 cases and 277 controls. The overall age-adjusted relative odds of prostate cancer associated with the number of (CAG) repeats as a continuous variable was 0.97 [95% confidence interval (CI), 0.92-1.03], suggesting a 3% decrease in risk of prostate cancer for each additional (CAG) repeat. Further analyses identified several subgroups at increased risk. These were men with less than the median number of CAG repeats ( 16 repeats. Overall, those men who had or = 22; GGN, > 16). These data suggest that determination of both androgen receptor repeats within germ-line DNA may be useful in assessing an individual's risk of developing prostate cancer.

The Limits of Reductionism in Medicine: Could Systems Biology Offer an Alternative?

Abstract: In the first of a two part series, Ahn and colleagues discuss the reductionist approach pervading medicine and explain how a systems approach (as advocated by systems biology) may complement reductionism.