Statistical database analysis of the role of loop dynamics for protein–protein complex formation and allostery

Gu, Yina; Li, Dawei; Brüschweiler, Rafael

doi:10.1093/bioinformatics/btx070

Cited by 6 publications

(9 citation statements)

References 17 publications

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“…S5 ) which are formed and broken over the course of the simulation. The contributions of hydrogen bonding to the conformation dynamics and lower event activity detected in regions populated by B – D is consistent with characterization of the Ω-loop as static 34 , 35 . The high variability of the hinge angles in the transition regions and the reversible C – D conformation change suggests C as a key loop conformation for Dio3 activity, which is supported by the locking of this conformation by T 4 binding (vide infra).…”

Section: Resultssupporting

confidence: 83%

Thyroxine binding to type III iodothyronine deiodinase

Bayse

Marsan

Garcia

et al. 2020

Sci Rep

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Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop’s N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I⋯Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I⋯O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins.

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Section: Resultssupporting

confidence: 83%

Thyroxine binding to type III iodothyronine deiodinase

Bayse

Marsan

Garcia

et al. 2020

Sci Rep

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“…As shown in the morphing simulation (Supporting Videos S2–3), the C'D loop elasticity plays a pivotal role when binding to pembrolizumab. The plasticity was further confirmed by a 500 ns molecular dynamics (MD) simulation of the reconstituted free 3RRQ** and bounded PD1 structures using the ToeLoop algorithm [54,55] . In the calculated MD trajectories, the C'D loop mobility was characterized by “fast” dynamics (Figure S7, Supporting Information).…”

Section: Resultsmentioning

confidence: 73%

Exploiting the Innate Plasticity of the Programmed Cell Death‐1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics**

et al. 2022

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Checkpoint blockade of the immunoreceptor programmed cell death-1 (PD1) with its ligand-1 (PDL1) by monoclonal antibodies such as pembrolizumab provided compelling clinical results in various cancer types, yet the molecular mechanism by which this drug blocks the PD1/PDL1 interface remains unclear. To address this question, we examined the conformational motion of PD1 associated with the binding of pembrolizumab. Our results revealed that the innate plasticity of both C'D and FG loops is crucial to form a deep binding groove (371 Å 3 ) across several distant epitopes of PD1. This analysis ultimately provided a rational-design to create pembrolizumab H3 loop mimics [RDYRFDMGFD] into β-hairpin scaffolds. As a result, a 20-residue long β-hairpin peptide 1 e was identified as a first-inclass potent PD1-inhibitor (EC 50 of 0.29 μM; K i of 41 nM).

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“…The flexible nature of the C'D loop was further confirmed by a 500 ns molecular dynamics (MD) simulation of the reconstituted apo-PD-1 and the bounded PD-1 structures using the ToeLoop algorithm (See Supplementary Figure S6). 44,45 According to the calculated MD trajectories, the C'D loop mobility was characterized by "fast" dynamics. The overall flexibility of this 14 residues loop [Phe 82 -Phe 95 ], as well as the distance between segment termini (dPhe82-Phe95 = 11.7 Å) in comparison to the longest C-C distance within the loop (dPro83-Arg94 = 16.3 Å) are characteristic features of a -type loop.…”

Section: Resultsmentioning

confidence: 99%

“…To better understand the plasticity of the PD-1 receptor, both structures apo-PD-1 remodeled (PDB: 3RRQ**) and the PD-1 excised from PDBs 5GGS and 5B8C have been tested for loop flexibility using ToeLoop. 44,45 Results from these MD simulations were exploited to estimate the difference of motions between loops (Supplementary Figure S6).…”

Section: Methods X-ray Crystal Structures Analysis and Interpretationmentioning

confidence: 99%

Bent to Bind: Exploiting the Programmed Cell Death-1 (PD-1) Receptor Plasticity to Design Pembrolizumab H3 Loop Mimics

Zaghouani¹,

Zhao²,

Richaud³

et al. 2021

Preprint

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Checkpoint blockade of the Programmed cell Death-1 (PD-1) immunoreceptor with its ligand 1 (PD-L1) by the monoclonal antibody pembrolizumab provided compelling clinical results among various cancer types, yet the molecular mechanism by which this drug blocks the PD-1:PD-L1 binding interface and reactivates exhausted T cells remains unclear. To address this question, we examined the conformational motion of PD-1 associated with the binding of pembrolizumab. The largely overlooked innate plasticity of both PD-1 C’D and FG loops appears crucial to closing in the receptor edges on the drug. Herein, we describe how PD-1 bends to initiate the formation of a deep binding groove (371 Å3) across several epitopes while engaging pembrolizumab. Our analysis ultimately provided a rational design for mimicking the pembrolizumab H3 loop [RDYRFDMGFD] as a PD-1 inhibitor. A series of H3 loop mimics were synthesized and their folding characterized by CD and NMR spectroscopy. As a result, a first-in-class b-hairpin peptide inhibitor of the PD-1/PD-L1 interface was identified (IC50 of 0.6 ± 0.2 μM). Overall, this study demonstrates that the dynamic groove formed between the C’D and FG loops of PD-1 is an attractive target for the development of peptide-based PD-1 inhibitors.

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Statistical database analysis of the role of loop dynamics for protein–protein complex formation and allostery

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 6 publications

References 17 publications

Thyroxine binding to type III iodothyronine deiodinase

Thyroxine binding to type III iodothyronine deiodinase

Exploiting the Innate Plasticity of the Programmed Cell Death‐1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics**

Bent to Bind: Exploiting the Programmed Cell Death-1 (PD-1) Receptor Plasticity to Design Pembrolizumab H3 Loop Mimics

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