A global Ramachandran score identifies protein structures with unlikely stereochemistry

Sobolev, Oleg V.; Afonine, Pavel V.; Moriarty, Nigel W.; Hekkelman, Maarten L.; Joosten, Robbie P.; Perrakis, Anastassis; Adams, Paul D.

doi:10.1101/2020.03.26.010587

Cited by 10 publications

(9 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All structures were validated using MolProbity (42) as implemented within PHENIX, including the recently introduced Rama-Z measure (43). The refinement statistics for the coordinate models are given in Table 1.…”

Section: Refinement Using Phenix-opls3ementioning

confidence: 99%

2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942

Greber¹,

Remis²,

Ali³

et al. 2021

Biophysical Journal

View full text Add to dashboard Cite

The human CDK-activating kinase (CAK), composed of CDK7, cyclin H, and MAT1, is involved in the control of transcription initiation and the cell cycle. Because of these activities, it has been identified as a promising target for cancer chemotherapy. A number of CDK7 inhibitors have entered clinical trials, among them ICEC0942 (also known as CT7001). Structural information can aid in improving the affinity and specificity of such drugs or drug candidates, reducing side effects in patients. Here, we have determined the structure of the human CAK in complex with ICEC0942 at 2.5 Å -resolution using cryogenic electron microscopy. Our structure reveals conformational differences of ICEC0942 compared with previous X-ray crystal structures of the CDK2-bound complex, and highlights the critical ability of cryogenic electron microscopy to resolve structures of drug-bound protein complexes without the need to crystalize the protein target.

show abstract

Section: Refinement Using Phenix-opls3ementioning

confidence: 99%

2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942

Greber¹,

Remis²,

Ali³

et al. 2021

Biophysical Journal

View full text Add to dashboard Cite

show abstract

“…Since the number of high-resolution cryo-EM structures is limited, we wondered whether the Ramachandran Z -scores 28 of our structures ( Table 1 ) would follow the distribution of Ramachandran Z -ranges as observed for crystal structures in a similar resolution regime 29 . The Ramachandran Z -scores of the Sr BDH1 and So BDH2 structures are in the expected region of crystal structures of similar resolution.…”

Section: Resultsmentioning

confidence: 99%

Rapid high-resolution structure analysis of small, biotechnologically relevant enzymes by cryo-electron microscopy

Dimos

Helmer

et al. 2021

Preprint

View full text Add to dashboard Cite

Enzyme catalysis has emerged as a key technology for developing efficient, sustainable processes in the chemical, biotechnological and pharmaceutical industries. Plants provide large and diverse pools of biosynthetic enzymes that facilitate complex reactions, such as the formation of intricate terpene carbon skeletons, with exquisite specificity. High-resolution structural analysis of these enzymes is crucial to understand their mechanisms and modulate their properties by targeted engineering. Although cryo-electron microscopy (cryo-EM) has revolutionized structural biology, its applicability to high-resolution structure analysis of comparatively small enzymes is so far largely unexplored. Here, we show that cryo-EM can reveal the structures of ~120 kDa plant borneol dehydrogenases at or below 2 Å resolution, paving the way for the fast development of new biocatalysts that provide access to bioactive terpenes and terpenoids.

show abstract

“…Homology modelling and loop refinement functionalities of the PrimeX tool in Schrodinger platform (Schrödinger, LLC, New York, NY, 2020) were used for attaining the full structure, followed by energy minimisation. Quality of the resultant structure was assessed using Ramachandran Plot [35]. The final GRIM-19 model was subjected to blind protein-protein docking with HtrA2 trimer model.…”

Section: Molecular Modelling Of Grim-19 and Its Docking With Htra2mentioning

confidence: 99%

Elucidating the role of GRIM-19 as a substrate and allosteric activator of pro-apoptotic serine protease HtrA2

Kummari

Dutta

Patil

et al. 2021

Biochemical Journal

View full text Add to dashboard Cite

HtrA2 (High-temperature requirement A2) and GRIM-19 (Gene associated with retinoic and interferon-induced mortality 19 protein) are involved in various biological functions with their deregulation leading to multiple diseases. Although it is known that the interaction between GRIM-19 with HtrA2 promotes pro-apoptotic activity of the latter, the mechanistic details remained elusive till date. Moreover, designing allosteric modulators of HtrA2 remains obscure due to lack of adequate information on the mode of interaction with its natural substrates cum binding partners. Therefore, in this study, we have unfolded the interaction between HtrA2 and GRIM-19 so as to understand its subsequent functional repercussions. Using in silico analyses and biochemical assays, we identified the region in GRIM-19 that is involved in protein-protein interaction with HtrA2. Furthermore, we have presented a comprehensive illustration of HtrA2’s cleavage site specificity. Quantitative analysis using enzyme kinetics underscored the role of GRIM-19 in significant allosteric activation of HtrA2. Overall, this is an extensive study that not only defines HtrA2-GRIM-19 interaction, but also creates a framework for developing strategies toward allosteric regulation of HtrA2 for future therapeutic interventions.

show abstract

A global Ramachandran score identifies protein structures with unlikely stereochemistry

Cited by 10 publications

References 45 publications

2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942

2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942

Rapid high-resolution structure analysis of small, biotechnologically relevant enzymes by cryo-electron microscopy

Elucidating the role of GRIM-19 as a substrate and allosteric activator of pro-apoptotic serine protease HtrA2

Contact Info

Product

Resources

About