Molecular Modeling Insights into the Structure and Behavior of Integrins: A Review

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Jan 21

PMID 36672259

Authors

Igor Tvaroska

Stanislav Kozmon

Juraj Kona

Affiliations

Soon will be listed here.

Abstract

Integrins are heterodimeric glycoproteins crucial to the physiology and pathology of many biological functions. As adhesion molecules, they mediate immune cell trafficking, migration, and immunological synapse formation during inflammation and cancer. The recognition of the vital roles of integrins in various diseases revealed their therapeutic potential. Despite the great effort in the last thirty years, up to now, only seven integrin-based drugs have entered the market. Recent progress in deciphering integrin functions, signaling, and interactions with ligands, along with advancement in rational drug design strategies, provide an opportunity to exploit their therapeutic potential and discover novel agents. This review will discuss the molecular modeling methods used in determining integrins' dynamic properties and in providing information toward understanding their properties and function at the atomic level. Then, we will survey the relevant contributions and the current understanding of integrin structure, activation, the binding of essential ligands, and the role of molecular modeling methods in the rational design of antagonists. We will emphasize the role played by molecular modeling methods in progress in these areas and the designing of integrin antagonists.

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References

Hamidi H, Pietila M, Ivaska J . The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer. 2016; 115(9):1017-1023. PMC: 5117799. DOI: 10.1038/bjc.2016.312. View

Costa A, Campos D, Reis C, Gomes C . Targeting Glycosylation: A New Road for Cancer Drug Discovery. Trends Cancer. 2020; 6(9):757-766. DOI: 10.1016/j.trecan.2020.04.002. View

Schmidt C, Chen T, Lauffenburger D . Simulation of integrin-cytoskeletal interactions in migrating fibroblasts. Biophys J. 1994; 67(1):461-74. PMC: 1225379. DOI: 10.1016/S0006-3495(94)80502-8. View

Dhavalikar P, Robinson A, Lan Z, Jenkins D, Chwatko M, Salhadar K . Review of Integrin-Targeting Biomaterials in Tissue Engineering. Adv Healthc Mater. 2020; 9(23):e2000795. PMC: 7960574. DOI: 10.1002/adhm.202000795. View

Trnka T, Tvaroska I, Koca J . Automated Training of ReaxFF Reactive Force Fields for Energetics of Enzymatic Reactions. J Chem Theory Comput. 2017; 14(1):291-302. DOI: 10.1021/acs.jctc.7b00870. View

Zhao J, Santino F, Giacomini D, Gentilucci L . Integrin-Targeting Peptides for the Design of Functional Cell-Responsive Biomaterials. Biomedicines. 2020; 8(9). PMC: 7555639. DOI: 10.3390/biomedicines8090307. View

Lin F, Li J, Xie Y, Zhu J, Nguyen T, Zhang Y . A general chemical principle for creating closure-stabilizing integrin inhibitors. Cell. 2022; 185(19):3533-3550.e27. PMC: 9494814. DOI: 10.1016/j.cell.2022.08.008. View

Sen M, Yuki K, Springer T . An internal ligand-bound, metastable state of a leukocyte integrin, αXβ2. J Cell Biol. 2014; 203(4):629-42. PMC: 3840939. DOI: 10.1083/jcb.201308083. View

Isaji T, Sato Y, Zhao Y, Miyoshi E, Wada Y, Taniguchi N . N-glycosylation of the beta-propeller domain of the integrin alpha5 subunit is essential for alpha5beta1 heterodimerization, expression on the cell surface, and its biological function. J Biol Chem. 2006; 281(44):33258-67. DOI: 10.1074/jbc.M607771200. View

10.

White D, Kurpios N, Zuo D, Hassell J, Blaess S, Mueller U . Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 2004; 6(2):159-70. DOI: 10.1016/j.ccr.2004.06.025. View

11.

Webb B, Sali A . Protein Structure Modeling with MODELLER. Methods Mol Biol. 2020; 2199:239-255. DOI: 10.1007/978-1-0716-0892-0_14. View

12.

Nair S, Ghosh K, Kulkarni B, Shetty S, Mohanty D . Glanzmann's thrombasthenia: updated. Platelets. 2002; 13(7):387-93. DOI: 10.1080/0953710021000024394. View

13.

Zhao Y, Schultz N, Truhlar D . Design of Density Functionals by Combining the Method of Constraint Satisfaction with Parametrization for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions. J Chem Theory Comput. 2015; 2(2):364-82. DOI: 10.1021/ct0502763. View

14.

Schreiber R, Old L, Smyth M . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331(6024):1565-70. DOI: 10.1126/science.1203486. View

15.

Raab-Westphal S, Marshall J, Goodman S . Integrins as Therapeutic Targets: Successes and Cancers. Cancers (Basel). 2017; 9(9). PMC: 5615325. DOI: 10.3390/cancers9090110. View

16.

Chng C, Tan S . Leukocyte integrin αLβ2 transmembrane association dynamics revealed by coarse-grained molecular dynamics simulations. Proteins. 2011; 79(7):2203-13. DOI: 10.1002/prot.23044. View

17.

Graham K, Fleming F, Halasz P, Hewish M, Nagesha H, Holmes I . Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands. J Gen Virol. 2005; 86(Pt 12):3397-3408. DOI: 10.1099/vir.0.81102-0. View

18.

Goodsell D, Lauble H, Stout C, Olson A . Automated docking in crystallography: analysis of the substrates of aconitase. Proteins. 1993; 17(1):1-10. DOI: 10.1002/prot.340170104. View

19.

Eke I, Cordes N . Focal adhesion signaling and therapy resistance in cancer. Semin Cancer Biol. 2014; 31:65-75. DOI: 10.1016/j.semcancer.2014.07.009. View

20.

Marinelli L, Gottschalk K, Meyer A, Novellino E, Kessler H . Human integrin alphavbeta5: homology modeling and ligand binding. J Med Chem. 2004; 47(17):4166-77. DOI: 10.1021/jm030635j. View