Stanley Opella – The conqueror of membrane protein structure

Abstract

Proteins that span biological membranes perform some of the most important biochemical processes that are vital for life. Understanding their structural organisation is a prerequisite for developing drugs for treatment of diseases including various forms of cancer, cardiovascular disease, disorders of the immune and nervous systems etc. However, unravelling the detailed structural organisation of these proteins in their native membrane bound state has been virtually impossible. Amongst membrane proteins that are particularly important for drug development are G-protein-coupled receptors (GPCRs) which are a large family of membrane proteins. Approximately 50% of the currently available medications target this class of proteins. Detailed structural characterisation of these proteins is vital for developing drugs that can interact with specific binding sites and control their activities. Unfortunately, the most powerful technique for determining the three-dimensional structure of proteins, namely X-ray crystallography, cannot be readily used since membrane proteins are difficult to crystallise. To aid crystallisation of membrane proteins, it is necessary to remove the lipids that surround the protein, by adding detergents. Additional procedures used to obtain crystals include forming complexes with other proteins or even through insertions or deletions of entire protein domains within the GPCR protein. However, these manipulations could alter the structure of the GPCR which can hinder or slow down the process of designing drugs that require precise knowledge of the binding site within the intact protein molecule in its native lipid membrane environment. Consequently, one of the greatest challenge facing structural biologists is to be able to conquer the structure of membrane proteins without resorting to such manipulations which are often referred to as “divide and conquer”. The man who has been successful in meeting this challenge is Stanley Opella (Fig. 1) and his group at the University of California at San Diego [1]. They used solid state NMR spectroscopy to determine the complete three-dimensional structure of a GPCR protein, called CXCR1, intact in its membrane environment (Fig. 2). This is the first time the highresolution structure of such a large protein has been elucidated in its biologically relevant state. For this reason, Stanley Opella can be rightly described as the conqueror of membrane protein structure. This landmark achievement paves the way for determining the structure of not only other GPCRs but of other membrane proteins in their native membrane environment. Previously X-ray crystallography has been used to gain information on the structure of GPCR’s which helped to provide better insights into the mechanism of action of this class of proteins. The importance of this work was recognised through the award of a Nobel Prize in Chemistry to Robert Lefkowitz and Brian Kobilka [2,3]. The breakthrough made by Stanley Opella and his group will further advance our understanding of GPCRs and accelerate the development of life saving drugs.