Impacts of Mutations in the P-Loop on Conformational Alterations of KRAS Investigated with Gaussian Accelerated Molecular Dynamics Simulations DOI Creative Commons
Shuhua Shi,

Linqi Zheng,

Yonglian Ren

и другие.

Molecules, Год журнала: 2023, Номер 28(7), С. 2886 - 2886

Опубликована: Март 23, 2023

G12 mutations heavily affect conformational transformation and activity of KRAS. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations were performed on the GDP-bound wild-type (WT), G12A, G12D, G12R KRAS to probe mutation-mediated impacts alterations The results indicate that three obviously structural flexibility internal switch domains. analyses free energy landscapes (FELs) suggest induce more states lead disordered principal component analysis shows change concerted motions behavior domains mostly overlap with binding region its effectors. Thus, high disorder motion changes induced by interaction network GDP signifies instability in interactions magnesium ion domain SW1 drives state This work is expected provide theoretical aids for understanding function

Язык: Английский

Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery DOI Creative Commons

Xin Qiao,

Xiaolong Li, Mingyang Zhang

и другие.

Pharmacological Research, Год журнала: 2025, Номер 212, С. 107574 - 107574

Опубликована: Янв. 2, 2025

G protein-coupled receptors (GPCRs) represent the largest family of membrane and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including proteins (such as Gi/o, Gs, G12, Gq) β-arrestins β-arrestin 1 2) to mediate diverse cellular physiological responses. Biased signaling allows specific activation certain pathways from full range receptors' capabilities. Targeting more variable allosteric sites, which spatially conserved orthosteric represents a novel approach in biased GPCR drug discovery, leading innovative strategies targeting GPCRs. Notably, emergence cryptic sites on has expanded repertoire available improved receptor subtype selectivity. Here, we conduct summary recent progress structural determination elucidate mechanisms induced by modulators. Additionally, discuss means identify design modulators based through structure-based design, is an advanced pharmacotherapeutic treating GPCR-associated diseases.

Язык: Английский

Процитировано

3
Negative allosteric modulation of the glucagon receptor by RAMP2 DOI Creative Commons
Kaavya Krishna Kumar, Evan S. O’Brien,

Chris Habrian

и другие.

Cell, Год журнала: 2023, Номер 186(7), С. 1465 - 1477.e18

Опубликована: Март 1, 2023

Язык: Английский

Процитировано

32
Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5 DOI Creative Commons
Mingyu Li,

Xiaobing Lan,

Xinchao Shi

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 30, 2024

Two-thirds of signaling hormones and one-third approved drugs exert their effects by binding modulating the G protein-coupled receptors (GPCRs) activation. While activation mechanism for monomeric GPCRs has been well-established, little is known about in dimeric form. Here, combining transition pathway generation, extensive atomistic simulation-based Markov state models, experimental assays, we reveal an asymmetric, stepwise millisecond allosteric metabotropic glutamate receptor subtype 5 (mGlu5), obligate class C GPCR. The dynamic picture presented that agonist induces ectodomains compaction, amplified precise association cysteine-rich domains, ultimately loosely bringing intracellular 7-transmembrane (7TM) domains into proximity establishing asymmetric TM6-TM6 interface. active inter-domain interface enhances intra-domain flexibility, triggering micro-switches crucial downstream signal transduction. Furthermore, show positive modulator stabilizes both 7TM open, extended ICL2 conformation. This stabilization leads to formation a pseudo-cavity composed ICL2, ICL3, TM3, C-terminus, which facilitates protein coordination. Our strategy may be generalizable characterizing events other systems. Activation form remains enigmatic. authors present characterization mGlu5, GPCR, suggesting mechanism.

Язык: Английский

Процитировано

11
New Insights into the Structure and Function of Class B1 GPCRs DOI Creative Commons
Brian P. Cary, Xin Zhang, Jianjun Cao

и другие.

Endocrine Reviews, Год журнала: 2022, Номер 44(3), С. 492 - 517

Опубликована: Дек. 22, 2022

Abstract G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors. Class B1 GPCRs constitute a subfamily 15 that characteristically contain large extracellular domains (ECDs) and respond to long polypeptide hormones. critical regulators homeostasis, and, as such, many important drug targets. While most transmembrane proteins, including GPCRs, recalcitrant crystallization, recent advances in cryo-electron microscopy (cryo-EM) have facilitated rapid expansion structural understanding membrane proteins. As testament this success, structures for all class bound proteins been determined by cryo-EM past 5 years. Further uncovered dynamics these receptors, ligands, signaling partners. Here, we examine underpinnings with an emphasis on structure–function relationships.

Язык: Английский

Процитировано

38
Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations DOI Creative Commons

Huayin Bao,

Wei Wang,

Haibo Sun

и другие.

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2023, Номер 38(1)

Опубликована: Апрель 14, 2023

Mutations highly affect the structural flexibility of two switch domains in M-RAS considered an important target anticancer drug design. Gaussian accelerated molecular dynamics (GaMD) simulations were applied to probe effect mutations P40D, D41E, and P40D/D41E/L51R on conformational transition from GTP-bound M-RAS. The analyses free energy landscapes (FELs) not only reveal that three induce less energetic states than wild-type (WT) but also verify are extremely disordered. Principal component analysis (PCA) suggest greatly collective motions mostly overlap with binding regions its effectors, which turn disturbs activity interaction network between GTP show high instability hydrogen bonding interactions (HBIs) residue 41 Y42 domain I drives disordered domains. This work is expected provide a mechanism for deeply understanding function future design towards treatment cancers.

Язык: Английский

Процитировано

22
Roles of Accelerated Molecular Dynamics Simulations in Predictions of Binding Kinetic Parameters DOI
Jianzhong Chen, Wei Wang,

Haibo Sun

и другие.

Mini-Reviews in Medicinal Chemistry, Год журнала: 2024, Номер 24(14), С. 1323 - 1333

Опубликована: Янв. 24, 2024

Rational predictions on binding kinetics parameters of drugs to targets play significant roles in future drug designs. Full conformational samplings are requisite for accurate kinetic parameters. In this review, we mainly focus the applications enhanced sampling technologies calculations and residence time drugs. The methods involved molecular dynamics simulations applied not only probe changes but also reveal that is efficiency. For special attention paid accelerated (aMD) Gaussian aMD (GaMD) have been adopted predict association or disassociation rate constant. We expect review can provide useful information design.

Язык: Английский

Процитировано

9
Exploring the constitutive activation mechanism of the class A orphan GPR20 DOI
Mingyang Zhang,

Jian‐Yang Ao,

Ning Liu

и другие.

Acta Pharmacologica Sinica, Год журнала: 2024, Номер unknown

Опубликована: Сен. 10, 2024

Язык: Английский

Процитировано

8
Markov State Models and Molecular Dynamics Simulations Reveal the Conformational Transition of the Intrinsically Disordered Hypervariable Region of K-Ras4B to the Ordered Conformation DOI
Hao Zhang, Duan Ni,

Jigang Fan

и другие.

Journal of Chemical Information and Modeling, Год журнала: 2022, Номер 62(17), С. 4222 - 4231

Опубликована: Авг. 22, 2022

K-Ras4B, the most frequently mutated Ras isoform in human tumors, plays a vital part cell growth, differentiation, and survival. Its tail, C-terminal hypervariable region (HVR), is involved anchoring K-Ras4B at cellular plasma membrane isoform-specific protein–protein interactions signaling. In inactive guanosine diphosphate-bound state, intrinsically disordered HVR interacts with catalytic domain effector-binding region, rendering its autoinhibited state. Activation releases from domain, ensemble favoring an ordered α-helical structure. The large-scale conformational transition of to conformation remains poorly understood. Here, we deploy computational scheme that integrates path-generation algorithm, extensive molecular dynamics simulation, Markov state model analysis investigate landscape pathway. Our findings reveal stepwise pathway for uncover several key substates along Importantly, between are unraveled, highlighting pathogenesis mild mutations congenital developmental anomaly syndromes. Together, these provide deeper understanding mechanism regulation activity atomic level.

Язык: Английский

Процитировано

29
Computational elucidation of allosteric communication in proteins for allosteric drug design DOI
Duan Ni, Yaqin Liu, Ren Kong

и другие.

Drug Discovery Today, Год журнала: 2022, Номер 27(8), С. 2226 - 2234

Опубликована: Март 18, 2022

Язык: Английский

Процитировано

28
Binding modes of GDP, GTP and GNP to NRAS deciphered by using Gaussian accelerated molecular dynamics simulations DOI

Huayin Bao,

W. Wang,

H.B. Sun

и другие.

SAR and QSAR in environmental research, Год журнала: 2023, Номер 34(1), С. 65 - 89

Опубликована: Янв. 2, 2023

Probing binding modes of GDP, GTP and GNP to NRAS are significance for understanding the regulation mechanism on activity RAS proteins. Four separate Gaussian accelerated molecular dynamics (GaMD) simulations were performed apo, GDP-, GTP- GNP-bound NRAS. Dynamics analyses suggest that three ligands highly affects conformational states switch domains from NRAS, which disturbs its effectors. The free energy landscapes (FELs) indicate induces more energetic compared apo but presence makes ordered than GDP GNP. information interaction networks with reveals π-π residue F28 salt bridge interactions K16 D119 stabilize Meanwhile magnesium ion plays a role in is favourable associations This work expected provide useful deeply function

Язык: Английский

Процитировано

15