resolution prmt5 structure  (Merck & Co)

Journal: Journal of Chemical Theory and Computation

Article Title: Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug Targets

doi: 10.1021/acs.jctc.5c02016

Figure Lengend Snippet: Cryptic pockets and the case of protein arginine methyltransferase 5. (A) Illustrates how early experimentally resolved structures of unliganded drug targets lacked satisfactory pockets for drug discovery but dynamic structural changes revealed cryptic pockets enabling ligand binding. (B) Shows PRMT5′s functional “double E” loop (red), cofactor SAM (magenta) and an example substrate arginine (cyan). An overlay of experimentally resolved structures with the EE loop in its default position is also shown, along with an experimentally resolved state (PDB ID 6UXY ) with the exposed cryptic pocket (circled in red). (C) Shows a structure and sequence alignment (EE loop boxed in black, Clustal2 coloring) of PRMT5 with the other PRMT family members, highlighting EE loop conservation.

Article Snippet: To limit bias arising from different research groups and crystallization conditions, the highest resolution PRMT5 structure resolved by Merck & Co., who solved the allosteric states, showing the EE loop in its default conformation was selected as starting structure: PDB ID 7KIC .

Techniques: Drug discovery, Ligand Binding Assay, Functional Assay, Sequencing

Journal: Journal of Chemical Theory and Computation

Article Title: Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug Targets

doi: 10.1021/acs.jctc.5c02016

Figure Lengend Snippet: SLICE sampling method based on close contact CVs and OPES Explore biases. Here, the key steps involved in the developed sampling method SLICE are depicted. Knowledge of the target biology is used first to manually set the start and end sequence position to define a region of interest, upon which close contacts are automatically defined and disrupted through OPES Explore biases in a molecular dynamics simulation. PRMT5 is shown as an example here, with panel 4 illustrating various sampled conformations of the EE loop and its close contacts.

Article Snippet: To limit bias arising from different research groups and crystallization conditions, the highest resolution PRMT5 structure resolved by Merck & Co., who solved the allosteric states, showing the EE loop in its default conformation was selected as starting structure: PDB ID 7KIC .

Techniques: Sampling, Sequencing

Journal: Journal of Chemical Theory and Computation

Article Title: Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug Targets

doi: 10.1021/acs.jctc.5c02016

Figure Lengend Snippet: Pocket analysis and results for PRMT5. (A) Depicts our approach to define ligandable cryptic pockets, where binding regions identified by SiteMap (cyan spheres, SiteScore > 1.0, DScore > 1.0) in the SLICE simulations are only retained if there is no significant (>20%) overlap with binding regions identified by SiteMap in the standard MD simulations. (B) Shows the resulting identified ligandable cryptic pocket for PRMT5 (cyan spheres), along with the crystallized (red, PDB ID 7KIC , 6UXY, and 6UXX) and example simulated (black) EE loop conformations. For reference, the cocrystallized allosteric ligands (black sticks) are also shown but they were not part of the simulations or pocket definitions.

Article Snippet: To limit bias arising from different research groups and crystallization conditions, the highest resolution PRMT5 structure resolved by Merck & Co., who solved the allosteric states, showing the EE loop in its default conformation was selected as starting structure: PDB ID 7KIC .

Techniques: Binding Assay

Journal: Journal of Chemical Theory and Computation

Article Title: Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug Targets

doi: 10.1021/acs.jctc.5c02016

Figure Lengend Snippet: Mechanistic insights into cryptic pocket formation in the targets studied, showing illustrative snapshots from SLICE simulations in which cryptic pockets formed, highlighting the bias region (red), cryptic ligand (transparent red) and key residues (boxed). (A) PRMT5: D442-R604 dissociate first to facilitate F440 movement. (B) PRMT6: M373-H163 disperse followed by L161 displacement. (C) Abl1: rearrangements between M388-I360 and W405-A365 enable R386 to approach E286, facilitated by A380 and V299 displacement, causing R386 to disrupt E286- K271. (D) SMARCA2: E890-K857 disperse and M856 readjusts. (E) PI3Kα: H940 dissociates from E1012 and Q809, enabling the loop/helix segment to vacate the cryptic pocket area.

Article Snippet: To limit bias arising from different research groups and crystallization conditions, the highest resolution PRMT5 structure resolved by Merck & Co., who solved the allosteric states, showing the EE loop in its default conformation was selected as starting structure: PDB ID 7KIC .

Techniques: