دورية أكاديمية
Insight into the mechanism of molecular recognition between human Integrin‑Linked Kinase and Cpd22 and its implication at atomic level
| العنوان: | Insight into the mechanism of molecular recognition between human Integrin‑Linked Kinase and Cpd22 and its implication at atomic level |
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| المؤلفون: | García-Marín, Javier, Rodríguez-Puyol, Diego, Vaquero, Juan J. |
| المساهمون: | Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, García-Marín, Javier 0002-5883-4783, Rodríguez-Puyol, Diego, Vaquero, Juan J. |
| بيانات النشر: | Springer |
| سنة النشر: | 2022 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| مصطلحات موضوعية: | Integrin-linked kinase, ILK, Cpd22, Molecular dynamics, PELE, Pseudokinase |
| الوصف: | 15 p.-7 fig.-1 tab.1 graph. abst. ; Pseudokinases have received increasing attention over the past decade because of their role in different physiological phenomena. Although pseudokinases lack several active-site residues, thereby hindering their catalytic activity, recent discoveries have shown that these proteins can play a role in intracellular signaling thanks to their non-catalytic functions. Integrin-linked kinase (ILK) was discovered more than two decades ago and was subsequently validated as a promising target for neoplastic diseases. Since then, only a few small-molecule inhibitors have been described, with the V-shaped pyrazole Cpd22 being the most interesting and characterized. However, little is known about its detailed mechanism of action at atomic level. In this study, using a combination of computational chemistry methods including PELE calculations, docking, molecular dynamics and experimental surface plasmon resonance, we were able to prove the direct binding of this molecule to ILK, thus providing the basis of its molecular recognition by the protein and the effect over its architecture. Our breakthroughs show that Cpd22 binding stabilizes the ILK domain by binding to the pseudo-active site in a similar way to the ATP, possibly modulating its scaffolding properties as pseudokinase. Moreover, our results explain the experimental observations obtained during Cpd22 development, thus paving the way to the development of new chemical probes and potential drugs. ; Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. We gratefully acknowledge spanish Ministerio de Ciencia e Innovación (MICINN/PID2020-115128RB-I00), Instituto de Salud Carlos III (FEDER funds, RICORS2040/Kidney Disease, RD21/0005/0005 and RD21/0005/0023), Comunidad de Madrid (NOVELREN-CM/B2017/BMD3751 and S2017/BMD3751) for financial support. ; Peer reviewed |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0920-654X 1573-4951 |
| العلاقة: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115128RB-I00/ES/ESTRATEGIAS DE QUIMICA MEDICA EN LA ENFERMEDAD RENAL. NUEVOS CROMOFOROS PARA TINCION CELULAR Y BIOIMAGEN/; NOVELREN-CM/B2017/BMD3751; NOVELREN-CM/S2017/BMD3751; Publisher's version; https://doi.org/10.1007/s10822-022-00466-1Test; Sí; Journal of Computer-Aided Molecular Design (2022); http://hdl.handle.net/10261/276427Test; http://dx.doi.org/10.13039/501100004837Test; http://dx.doi.org/10.13039/100012818Test; http://dx.doi.org/10.13039/501100003339Test; http://dx.doi.org/10.13039/501100004587Test |
| DOI: | 10.1007/s10822-022-00466-1 |
| DOI: | 10.13039/501100004837 |
| DOI: | 10.13039/100012818 |
| DOI: | 10.13039/501100003339 |
| DOI: | 10.13039/501100004587 |
| الإتاحة: | https://doi.org/10.1007/s10822-022-00466-1Test https://doi.org/10.13039/501100004837Test https://doi.org/10.13039/100012818Test https://doi.org/10.13039/501100003339Test https://doi.org/10.13039/501100004587Test http://hdl.handle.net/10261/276427Test |
| حقوق: | open |
| رقم الانضمام: | edsbas.A2A0C1E4 |
| قاعدة البيانات: | BASE |
| تدمد: | 0920654X 15734951 |
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| DOI: | 10.1007/s10822-022-00466-1 |