Break CDK2/Cyclin E1 Interface Allosterically with Small Peptides

Chen, Hao; Zhao, Yunjie; Li, Haotian; Zhang, Dongyan; Huang, Yanzhao; Shen, Qi; Duyne, Rachel Van; Kashanchi, Fatah; Zeng, Chen; Liu, Shiyong

doi:10.1371/journal.pone.0109154

Cited by 20 publications

(18 citation statements)

References 55 publications

(65 reference statements)

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“…MD simulations can be effective in understanding how the two mutations at position 130 perturb the protein structure. The accuracy in computational modeling and MD simulation has made it possible to study processes that are too fast to be observed experimentally [ 25 – 27 ]. These approaches have been successfully employed to address questions ranging from protein folding to drug design and screening [ 25 , 28 – 30 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation Reveals Insights into the Mechanism of Unfolding by the A130T/V Mutations within the MID1 Zinc-Binding Bbox1 Domain

2015

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The zinc-binding Bbox1 domain in protein MID1, a member of the TRIM family of proteins, facilitates the ubiquitination of the catalytic subunit of protein phosphatase 2A and alpha4, a protein regulator of PP2A. The natural mutation of residue A130 to a valine or threonine disrupts substrate recognition and catalysis. While NMR data revealed the A130T mutant Bbox1 domain failed to coordinate both structurally essential zinc ions and resulted in an unfolded structure, the unfolding mechanism is unknown. Principle component analysis revealed that residue A130 served as a hinge point between the structured β-strand-turn-β-strand (β-turn-β) and the lasso-like loop sub-structures that constitute loop1 of the ββα-RING fold that the Bbox1 domain adopts. Backbone RMSD data indicate significant flexibility and departure from the native structure within the first 5 ns of the molecular dynamics (MD) simulation for the A130V mutant (>6 Å) and after 30 ns for A130T mutant (>6 Å). Overall RMSF values were higher for the mutant structures and showed increased flexibility around residues 125 and 155, regions with zinc-coordinating residues. Simulated pKa values of the sulfhydryl group of C142 located near A130 suggested an increased in value to ~9.0, paralleling the increase in the apparent dielectric constants for the small cavity near residue A130. Protonation of the sulfhydryl group would disrupt zinc-coordination, directly contributing to unfolding of the Bbox1. Together, the increased motion of residues of loop 1, which contains four of the six zinc-binding cysteine residues, and the increased pKa of C142 could destabilize the structure of the zinc-coordinating residues and contribute to the unfolding.

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Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation Reveals Insights into the Mechanism of Unfolding by the A130T/V Mutations within the MID1 Zinc-Binding Bbox1 Domain

2015

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“…Four allosteric pockets in CDK2 have been identified crystallographically ( Table 3 ) with ligands bound in each of them [ 63–65 ]. Additionally, two allosteric pockets were putatively discovered by computational methods [ 66 , 67 ]. The best characterized allosteric pocket binds 8-anilino-1-naphthalene sulfonate (ANS), as confirmed by X-ray crystallography [ 63 ].…”

Section: Type III and Iv Allosteric Inhibitorsmentioning

confidence: 99%

“…The other allosteric pockets were discovered computationally at the interface of CDK2 and cyclin E, next to the T-loop [ 67 , 71 ]. Short 5-mer peptide DAALT bind to the interface allosteric pocket with the strongest affinity of K d = 0.5 μM to prevent the protein–protein interaction of CDK2 and cyclins [ 67 ]. Docking studies indicated that C177, K178, and Y180 are three key residues with the highest contribution toward binding these small peptides.…”

Section: Type III and Iv Allosteric Inhibitorsmentioning

confidence: 99%

“…Docking studies indicated that C177, K178, and Y180 are three key residues with the highest contribution toward binding these small peptides. These peptide inhibitors were suggested to induce the similar conformational change as cyclins, although this was never confirmed structurally [ 67 ]. Another allosteric pocket near the CDK2/cyclin A3 interface has been suggested [ 66 ].…”

Section: Type III and Iv Allosteric Inhibitorsmentioning

confidence: 99%

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Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†

Faber

Wang

Georg

2020

Biology of Reproduction

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Abstract Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1). From this evidence, we suggest that CDK2 could be a viable nonhormonal male contraceptive target. Finally, we review the literature of pertinent CDK2 inhibitors from the preclinical to clinical stages, mostly developed to treat various cancers. To date, there is no potent yet selective CDK2 inhibitor that could be repurposed as a contraceptive without appreciable off-target toxicity. To achieve selectivity for CDK2 over closely related kinases, developing compounds that bind outside the conserved adenosine triphosphate-binding site may be necessary.

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“…Here, we utilize the dynamical network analysis to investigate the structural characteristic of the bulb-type mannose binding protein 29 – 34 . The network analysis reveals that the polar residues on the surface with high closeness are responsible for the long-range recognition of dimer formation.…”

Section: Introductionmentioning

confidence: 99%

Network Analysis Reveals the Recognition Mechanism for Dimer Formation of Bulb-type Lectins

Zhao

Jian

Liu

et al. 2017

Sci Rep

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The bulb-type lectins are proteins consist of three sequential beta-sheet subdomains that bind to specific carbohydrates to perform certain biological functions. The active states of most bulb-type lectins are dimeric and it is thus important to elucidate the short- and long-range recognition mechanism for this dimer formation. To do so, we perform comparative sequence analysis for the single- and double-domain bulb-type lectins abundant in plant genomes. In contrast to the dimer complex of two single-domain lectins formed via protein-protein interactions, the double-domain lectin fuses two single-domain proteins into one protein with a short linker and requires only short-range interactions because its two single domains are always in close proximity. Sequence analysis demonstrates that the highly variable but coevolving polar residues at the interface of dimeric bulb-type lectins are largely absent in the double-domain bulb-type lectins. Moreover, network analysis on bulb-type lectin proteins show that these same polar residues have high closeness scores and thus serve as hubs with strong connections to all other residues. Taken together, we propose a potential mechanism for this lectin complex formation where coevolving polar residues of high closeness are responsible for long-range recognition.

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Break CDK2/Cyclin E1 Interface Allosterically with Small Peptides

Cited by 20 publications

References 55 publications

Molecular Dynamics Simulation Reveals Insights into the Mechanism of Unfolding by the A130T/V Mutations within the MID1 Zinc-Binding Bbox1 Domain

Molecular Dynamics Simulation Reveals Insights into the Mechanism of Unfolding by the A130T/V Mutations within the MID1 Zinc-Binding Bbox1 Domain

Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†

Network Analysis Reveals the Recognition Mechanism for Dimer Formation of Bulb-type Lectins

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