Abstract
Accurate predictions of 3-dimensional protein structures by AlphaFold2 is a game-changer for biology, especially for structural biology. Here we present the studies of several native chemokine receptors including CCR5, CCR9, CXCR2 and CXCR4 determined by X-ray crystallography, and their water-soluble QTY counter parts predicted by AlphaFold2. In the native structures, there are hydrophobic amino acids leucine (L), isoleucine (I), valine (V) and phenylalanine (F) in the transmembrane helices. These hydrophobic amino acids are systematically replaced by hydrophilic amino acids glutamine (Q), threonine (T), and tyrosine (Y). Thus, the QTY variants become water-soluble. We also present the superimposed structures of native CCR10, CXCR5, CXCR7 and an olfactory receptor OR1D2 and their water-soluble QTY variants. Since the CryoEM structural determinations for the QTY variants of CCR10QTY and OR1D2QTY are in progress, it will be of interest to compare them when the structures become available. The superimposed structures show remarkable similarity within RMSD 1Å–2Å despite significant sequence differences (~26%–~33%). We also show the differences of hydrophobicity patches between the native GPCR and their QTY variants. Our study provides insight into the subtle differences between the hydrophobic helices and hydrophilic helices, and may further stimulate designs of water-soluble membrane proteins and other aggregated proteins.
Highlights
The recent release of the highly accurate protein prediction software suite AlphaFold2 has revolutionized protein science, especially for structural biology [1,2,3]
AlphaFold2 significantly reduces the time-consuming and expensive molecular simulation process and broadens the applications to wider research and biotech communities [1,2,3]. These chemokine receptors were chosen because they play many critical roles in health and diseases, and have been well characterized [10,11,12,13]
Chemokine receptors CCR5, CCR9, CCR10, CXCR2, CXCR4, CXCR5 and CXCR7 are involved in various cancers initiation and metastasis, autoimmune diseases, viral infections and cytokine release syndrome, called “cytokine storm”
Summary
The recent release of the highly accurate protein prediction software suite AlphaFold has revolutionized protein science, especially for structural biology [1,2,3]. A similar prediction program RoseTTAFold made similar accurate protein structural predictions [4] Together, they provided a promising solution for the long-standing difficult protein folding problem, and limited predictions of protein–protein interactions, but they further stimulate research activities for protein design including design of water-soluble membrane proteins. AlphaFold significantly reduces the time-consuming and expensive molecular simulation process and broadens the applications to wider research and biotech communities [1,2,3]. These chemokine receptors were chosen because they play many critical roles in health and diseases, and have been well characterized [10,11,12,13]. The crystal structures of CXCR4, CCR5, CCR9 and CXCR2 have been published [14,15,16,17]. allowing direct comparison with the AlphaFold predicted water-soluble QTY variants
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