4um1

Engineered Ls-AChBP with alpha4-alpha4 binding pocket in complex with NS3573

spinqualitylabelsall models 4um1, resolution 2.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4um1 is a 5 chain structure with sequence from Lymnaea stagnalis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 09P, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ACHP_LYMST Binds to acetylcholine. Modulates neuronal synaptic transmission. Publication Abstract from PubMed Neuronal alpha4beta2 nicotinic acetylcholine receptors are attractive drug targets for psychiatric and neurodegenerative disorders and smoking cessation aids. Recently, a third agonist binding site between two alpha4 subunits in the (alpha4)3(beta2)2 receptor sub-population was discovered. In particular, three residues, H142, Q150, and T152, were demonstrated to be involved in the distinct pharmacology of the alpha4-alpha4 vs. alpha4-beta2 binding sites. To obtain insight into the 3-dimensional structure of the alpha4-alpha4 binding site, a surrogate protein reproducing alpha4-alpha4 binding characteristics was constructed by introduction of three point mutations, R104H, L112Q, and M114T, into the binding pocket of Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP). Co-crystallization with two agonists possessing distinct pharmacological profiles, NS3920 and NS3573, highlights the roles of the three residues in determining binding affinities and functional properties of ligands at the alpha4-alpha4 interface. Confirmed by mutational studies, our structures suggest a unique ligand-specific role of residue H142 on the alpha4 subunit. In the co-crystal structure of the mutated Ls-AChBP with the high efficacy ligand NS3920, the corresponding histidine forms an inter-subunit bridge that reinforces the ligand-mediated interactions between subunits. The structures further reveal that the binding site residues gain different and ligand-dependent interactions that could not be predicted based on wild-type Ls-AChBP structures in complex with the same agonists. The results show that an unprecedented correlation between binding in engineered AChBPs and functional receptors can be obtained and provide new opportunities for structure-based design of drugs targeting specific nAChR interfaces. AChBP Engineered to Mimic the alpha4-beta4 Binding Pocket in alpha4beta2 Nicotinic Acetylcholine Receptors Reveals Interface Specific Interactions Important for Binding and Activity.,Shahsavar A, Ahring PK, Olsen JA, Krintel C, Kastrup JS, Balle T, Gajhede M Mol Pharmacol. 2015 Jul 15. pii: mol.115.098061. PMID:26180047 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetylcholine binding protein 3D structures

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