The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued α-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued α-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.

CCR5-Maraviroc Structure: The chemokine receptor CCR5, a G protein–coupled receptor best known as a co-receptor during HIV-1 infection, is important in a variety of physiological processes. Tan et al. (p. 1387 , published online 12 September; see the Perspective by Klasse ) now report the high-resolution crystal structure of CCR5 bound to the HIV-1 entry inhibitor, Maraviroc. The structure suggests that Maraviroc acts as a noncompetitive inhibitor by binding to a region of CCR5 that is distinct from the binding site of HIV-1 and chemokines. Comparison of the structure of CCR5 with the other HIV-1 co-receptor, the chemokine receptor CXCR4, provides insight into the co-receptor selectivity of the virus.

Despite its apparent simplicity, the problem of quantifying the differences between two structures of the same protein or complex is nontrivial and continues evolving. In this chapter, we described several methods routinely used to compare computational models to...

Recent cancer genome deep sequencing efforts have revealed an unanticipated high frequency of mutations in G proteins and G-protein-coupled receptors (GPCRs) in most tumour types. A striking 4.2% of all tumour sequences deposited to date show activating mutations in GNAS (a complex locus that encodes Gα_s). Transforming mutations in GNAS have been well documented in human thyroid and pituitary tumours, and recent sequencing efforts have shown these mutations to be present in a wide variety of additional tumour types, including colon cancer, hepatocellular carcinoma, and parathyroid, ovarian, endometrial, biliary tract and pancreatic tumours. Mutually exclusive activating mutations in GNAQ or GNA11 (encoding Gα_q family members) occur in 5.6% of tumours, and they are present in ∼66% and ∼6% of melanomas arising in the eye and skin, respectively, where they can act as driver oncogenes. Hotspot mutations in Gα_s (R201 and Q227) as well as Gα_q and Gα₁₁ (R183 and Q209) disrupt the GTPase activity, thereby leading to constitutive activity and persistent signalling. Nearly 20% of human cancers harbour mutations in GPCRs. The most frequently mutated GPCRs include thyroid-stimulating hormone receptor (TSHR), Smoothened (SMO), glutamate metabotropic receptors (GRMs), members of the adhesion family of GPCRs and receptors for bioactive lipid mediators such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) that accumulate in the tumour microenvironment. Many GPCR mutations are still uncharacterized with respect to their potential contribution to tumorigenesis and cancer progression. Aberrant expression, overexpression or signal reprogramming of GPCRs and G proteins in tumour cells can contribute to cancer development and progression. These alterations may arise from cancer-specific changes in gene copy number, as well as from other genetic, epigenetic and post-translational changes resulting in higher protein expression, thereby enhancing tumour progression and metastasis. Detailed three dimensional structures of GPCRs in various activation states can now help to explain the functional impact of cancer-associated GPCR mutations, and guide the rational design of signalling-selective GPCR agonists, antagonists and allosteric modulators. G proteins, GPCRs and their linked signalling circuitry represent novel therapeutic targets for cancer prevention and treatment.

Molecular “go” signals reveal their secrets: Chemokines are proteins that direct how cells move within the body. For instance, chemokines help immune cells locate invading pathogens and ensure that cells position themselves correctly within a developing organ. Cells detect chemokines through G protein–coupled receptors on their surface; however, the molecular details of how these proteins interact remain unclear (see the Perspective by Standfuss). Qin et al. solved the crystal structure of the chemokine receptor CXCR4 bound to the viral chemokine vMIP-II. Burg et al. solved the crystal structure of a viral chemokine receptor bound to the chemokine domain of CX3CL1. Given the role of chemokines in a number of diseases, these results may help in future drug design. Science , this issue p. 1117 , p. 1113 ; see also p. 1071