In This Issue

11 A novel mechanism of ligand binding and release in the odorant binding protein 20 from the malaria mosquito Anopheles gambiae

Brian P. Ziemba, Emma J. Murphy, Hannah T. Edlin, and David N. M. Jones

AgamOBP20 is a key component of the mosquito olfactory system implicated in regulating responses to odor molecules present in human sweat that allow the mosquito to discriminate humans from other animals. The structure of AgamOBP20 reveals that two key α-helices form a flexible gate to the ligand binding pocket, which clamp down over the pocket when an odor molecule binds to lock the odor in place. Understanding how odorants change the structure of the protein is important in defining the binding sites for novel reagents designed to disrupt normal olfactory responses and prevent transmission of malaria. 1

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1 Structure and function of the SPRY/B30.2 domain proteins involved in innate immunity

Akshay A. D'Cruz, Jeffrey J. Babon, Raymond S. Norton, Nicos A. Nicola, and Sandra E. Nicholson

The SPRY domain is a protein interaction module involved in many important signaling pathways. We review the biochemical and structural properties of key SPRY domain-containing proteins involved in innate immunity. Currently, the SPRY family is divided into the SPRY-only and B30.2 sub-families. The latter is defined as a SPRY domain with an associated N-terminal “PRY” extension. Phylogenetic analysis and examination of the existing structural information, highlights a similar extension in SPRY-only proteins. This suggests that the two subfamilies are structurally equivalent and that the SPRY domain, as currently defined, is in fact only a segment of a larger structural domain which also incorporates an N-terminal extension. An understanding of the structure and evolutionary relationships within the SPRY domain family clarifies the domain architecture, which will be important for the design of future functional studies of this family of proteins. 2

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65 Detection of drug-induced conformational change of a transmembrane protein in lipid bilayers using site-directed spin labeling

Jessica L. Thomaston, Phuong A. Nguyen, Emily C. Brown, Mary Alice Upshur, Jun Wang, William F. DeGrado, and Kathleen P. Howard

The M2 protein is critical to the life cycle of influenza A and is the target of anti-viral drugs. This protein is membrane-bound and the packing of lipids around transmembrane domains impacts the range of states available to the protein. Here we spin-labeled sites throughout the protein and used electron paramagnetic resonance (EPR) spectroscopy to probe conformational changes induced upon the addition of adamantane drugs to M2 protein embedded in membranes. This study, in conjunction with structural data from other studies, expands our previous work to provide a more complete picture of the conformational changes of M2 upon drug binding. 3

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74 A comparison of successful and failed protein interface designs highlights the challenges of designing buried hydrogen bonds

P. Benjamin Stranges and Brian Kuhlman

One major goal of computational protein design is the creation of new protein-protein interactions. However, most designed interactions that appear favorable in the computational model fail to form when tested experimentally. This article looks at 153 designed interactions that did not form as predicted and compares them to five successful designs with X-ray crystal structures. Successful designs have low polar atom content at the interface and avoid burying interface-spanning hydrogen bonds. These observations point out that better sampling methods and energy function terms are needed to design native-like hydrogen bond networks from scratch. 4

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