Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect DOI Creative Commons
Xuan He,

Kui Du,

Yuanhao Wang

et al.

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: April 8, 2022

The Ras-specific guanine nucleotide exchange factors Son of Sevenless (SOS) regulates Ras activation by converting inactive GDP-bound to active GTP-bound states. catalytic activity is further allosterically regulated GTP−Ras bound a distal site through positive feedback loop. To address the mechanism underlying long-range allosteric K-Ras4B an additional GTP–Ras SOS, we employed molecular dynamics simulation G13D •SOS cat complex with and without . We found that binding GTP−K-Ras4B enhanced affinity between SOS , forming more stable conformational state. peeling away switch I from facilitated dissociation GDP, thereby contributing increased rate. community networks showed stronger edge connection upon binding, which represented interaction Moreover, transmitted signaling pathways though Cdc25 domain regulatory site. This study may provide in-depth for abnormal regulation

Language: Английский

Exploring the constitutive activation mechanism of the class A orphan GPR20 DOI
Mingyang Zhang,

Jian‐Yang Ao,

Ning Liu

et al.

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Language: Английский

Citations

5
Pharmacologically targeting intracellular allosteric sites of GPCRs for drug discovery DOI
Mingyang Zhang,

Xiaobing Lan,

Xiaolong Li

et al.

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103803 - 103803

Published: Oct. 17, 2023

Language: Английский

Citations

12
Exploring conformation changes of Janus kinase 2 pseudokinase mediated by mutations through Gaussian accelerated molecular dynamics and principal component analysis DOI

Huayin Bao,

Weikai He, Jianzhong Chen

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(20), P. 11115 - 11132

Published: Sept. 23, 2023

The pseudokinase domain (JH2) of the protein tyrosine kinase (Janus 2, JAK2) regulates activity a (JH1) in JAK2, which is further affected by mutations JH2. In this work, Gaussian accelerated molecular dynamics (GaMD) simulations followed construction free energy landscapes (FELs) and principal component analysis (PCA) were performed to study effect two V617F V617F/E596A on conformations ATP-bound dynamic analyses reveal that affect structural flexibility correlated motions JH2, meanwhile also change behavior P-loop αC-helix information from FELs unveils induce less states than JH2 WT one. interaction networks uncover salt bridge interactions ATP with K581, K677 R715 alter hydrogen bonding (HBIs) changes ATP-JH2 caused turn generate regulations JH1. This work expected provide significant theoretical helps for deeply understanding function drug design toward JAK2.Communicated Ramaswamy H. Sarma.

Language: Английский

Citations

11
Conformational States of the GDP- and GTP-Bound HRAS Affected by A59E and K117R: An Exploration from Gaussian Accelerated Molecular Dynamics DOI Creative Commons
Zhiping Yu, Zhen Wang,

Xiuzhen Cui

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(3), P. 645 - 645

Published: Jan. 30, 2024

The HRAS protein is considered a critical target for drug development in cancers. It vital effective to understand the effects of mutations on binding GTP and GDP HRAS. We conducted Gaussian accelerated molecular dynamics (GaMD) simulations free energy landscape (FEL) calculations investigate impacts two (A59E K117R) conformational states switch domain. Our findings demonstrate that these not only modify flexibility domains, but also affect correlated motions domains. Furthermore, significantly disrupt dynamic behavior leading change Additionally, impact domain’s interactions, including their hydrogen bonding with ligands electrostatic interactions magnesium ions. Since domains are crucial effectors, any alterations or will undoubtedly activity This research provides valuable information design drugs targeting

Language: Английский

Citations

4
The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator DOI Creative Commons

Jakob Mitgau,

Julius Franke,

Camilla Schinner

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: June 23, 2022

The adhesion G protein–coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the attractive pharmacological target. GPR126 is a mechano-sensor that translates binding of extracellular matrix (ECM) molecules to its N terminus into metabotropic intracellular signal. To date, structural requirements and character forces needed for this ECM-mediated activation are largely unknown. In study, we provide information by combining classic second-messenger detection with single-cell atomic force microscopy. We established monoclonal antibody targeting stimulate compared it through known ECM ligands, collagen IV laminin 211. As each ligand uses distinct mode action, can be regarded allosteric module fine-tune context-specific manner.

Language: Английский

Citations

19
Structural and energetic insights into the selective inhibition of PKMYT1 against WEE1 DOI

Xuesen Qi,

Guozhen Li,

Jiahai Liu

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(6), P. 3010 - 3018

Published: June 22, 2023

Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the WEE family and responsible for regulation CDK1 phosphorylation, has been considered promising therapeutic target cancer therapy. However, highly structural conservation ATP-binding sites poses challenge to design selective inhibitors PKMYT1. Here, molecular docking, multiple microsecond-length dynamics (MD) simulations end-point free energy calculations were performed uncover mechanism binding selectivity RP-6306 toward PKMYT1 over its homologous kinase WEE1. The specificity reported in previous experimental bioassays was clarified by MD calculations. Further, prediction indicated that largely derived from difference protein-ligand electrostatic interactions. per-residue decomposition suggested non-conserved gatekeeper residue hinge domain PKMYT1/WEE1, Thr187/Asn376, is critical factor In addition, water-mediated hydrogen bond formed between Gly191 at PKMYT1/RP-6306 complex, which absent WEE1/RP-6306 complex. This study expected offer useful information more potent inhibitors.Communicated Ramaswamy H. Sarma

Language: Английский

Citations

10
Allosteric Communication Mechanism in the Glucagon Receptor DOI Creative Commons
Wijnand J. C. van der Velden, Elizaveta Mukhaleva, Nagarajan Vaidehi

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108530 - 108530

Published: April 1, 2025

The glucagon receptor is dysregulated in metabolic disorders. Recent drug discovery has shown that agonists for the might be more promising as therapeutics. Allosteric modulation may pave an alternative way to initiate responses are required target these Here, we investigated allosteric communication mechanisms within using molecular dynamics simulations on five states. Results highlighted extracellular domain dynamic absence of orthosteric agonist. In presence a partial agonist, observed increased flexibility N-terminus compared full agonist bound receptor. Class B GPCR microswitches showed repacking going from inactive active state, allowing G protein coupling. and protein-bound Gαs both translational rotational movement N-terminus, core α5-helix, thereby forming key interactions between Lastly, region coupling was strongest intracellular negative modulator-bound agonist-bound protein-free state. residue positions predicted play significant role mechanism overlap with disease associated mutations. Overall, our study provides insights into class which sets foundation future design potential modulators targeting

Language: Английский

Citations

0
Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97 DOI Creative Commons
Hao Zhang,

Guojun Chu,

Gaoming Wang

et al.

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(9), P. 1856 - 1856

Published: Sept. 2, 2022

Adhesion G-protein-coupled receptors (aGPCRs)-a major family of GPCRs-play critical roles in the regulation tissue development and cancer progression. The orphan receptor GPR97, activated by glucocorticoid stress hormones, is a prototypical aGPCR. Although it has been established that palmitoylation C-terminal Go protein essential for Go's efficient engagement with active detailed allosteric mechanism remains to be clarified. Hence, we performed extensive large-scale molecular dynamics (MD) simulations GPR97-Go complex presence or absence palmitoylation. conformational landscapes analyzed Markov state models revealed overall conformation GPR97 preferred fully when interacting palmitoylated protein. Structural energetic analyses indicated can allosterically stabilize residues ligand-binding pocket increase affinity ligand GPR97. Furthermore, community network analysis suggests not only strengthens internal interactions between Gαo Gβγ, but also enhances coupling Our study provides mechanistic insights into aGPCRs via post-translational modifications protein, offers guidance future drug design aGPCRs.

Language: Английский

Citations

16
Deciphering Conformational Changes of the GDP-Bound NRAS Induced by Mutations G13D, Q61R, and C118S through Gaussian Accelerated Molecular Dynamic Simulations DOI Creative Commons
Zhiping Yu, Hong-Yi Su, Jianzhong Chen

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(17), P. 5596 - 5596

Published: Aug. 30, 2022

The conformational changes in switch domains significantly affect the activity of NRAS. Gaussian-accelerated molecular dynamics (GaMD) simulations three separate replicas were performed to decipher effects G13D, Q16R, and C118S on transformation GDP-bound analyses root-mean-square fluctuations cross-correlation maps indicated that structural flexibility motion modes involved binding NRAS effectors are highly altered by Q61R, C118Smutations. free energy landscapes (FELs) suggested mutations induce more energetic states than WT lead high disorder domains. FELs also different numbers sodium ions entering GDP regions compensate for electrostatic environments caused mutations, especially G13D. GDP-residue interactions revealed was attributable unstable hydrogen bonds between two residues, V29 D30. This work is expected provide information basis can aid deeply understanding target roles anticancer treatment.

Language: Английский

Citations

15
Designing drugs and chemical probes with the dualsteric approach DOI
Jinyin Zha, Jixiao He, Chengwei Wu

et al.

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(24), P. 8651 - 8677

Published: Jan. 1, 2023

Dualsteric modulators are praised for a balance of potency and selectivity, overcoming drug resistance, function bias, an easy scheme partial agonist. It could also be used to design fluorescent tracers study protein conformations.

Language: Английский

Citations

9