Estimating the “Steric Clash” atcisPeptide Bonds

2008 ◽  
Vol 112 (26) ◽  
pp. 7894-7902 ◽  
Author(s):  
Simon Mathieu ◽  
Romuald Poteau ◽  
Georges Trinquier
Keyword(s):  
Steric Clash

LY2874455 potently inhibits FGFR gatekeeper mutants and overcomes mutation-based resistance

2018 ◽  
Vol 54 (85) ◽  
pp. 12089-12092 ◽  
Author(s):  
Daichao Wu ◽  
Ming Guo ◽  
Xiaoli Min ◽  
Shuyan Dai ◽  
Meixiang Li ◽  
...  
Keyword(s):  
Steric Clash

LY2874455 can avoid a steric clash with the mutated gatekeeper residue in FGFR4.

In Silico modelling of Sensitivity to Novel Tyrosine Kinase Inhibitors of Highly Resistant Single and Polymutant BCR-ABL1.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3388-3388
Author(s):  
Sabrina Pricl ◽  
Don L Gibbons ◽  
Paola Posocco ◽  
Erik Laurini ◽  
Maurizio Fermaglia ◽  
...  
Keyword(s):  
In Silico ◽  
Research Funding ◽  
Double Mutant ◽  
3D Structure ◽  
Chronic Phase ◽  
Drug Binding ◽  
High Rate ◽  
Light Blue ◽  
Steric Clash ◽  
Mutational Status

Abstract Abstract 3388 We evaluated BCR-ABL1 mutational status in 70 pts with chronic myeloid leukemia in chronic phase after imatinib failure and during dasatinib therapyby DNA expansion of specific clones followed by DNA sequencing of ≥10 clones. Prior to dasatinib, 125 ABL1 kinase domain mutations at 113 amino acid positions were detected in 61/70 (87%) pts, including 38 (54%) with mutations in ≥20% of sequenced clones. Mutations conferring resistance to >1μ M imatinib (M244V, G250E, Q252H, Y253H, E255K/V, F359V, H396R, and T315I) were detected in 30 (43%) pts. Two or more mutations within the same clone (polymutants) were detected in 29/70 (41%) pts. These patients received dasatinib for a median of 19 mos (range, 2–52), during which dasatinib-resistant mutations (L248V/R, Q252H, E255K, V299L, T315I/A, and F317L/C/I/S/V) were detected in 10/32 (31%) assessable cases (5 with T315I). However, polymutants were observed in 16/32 (50%) pts, of whom 13 died in BP and 3 are alive in CP. Given the high frequency and variety of highly resistant polymutants observed in pts failing sequential imatinib-dasatinib therapy, we next performed 3D structural analyses to model the activity of dasatinib, AP23534, and PHA739358 against the most frequently encountered polymutants (Table1). Table 1. Free energy of binding (AGbind, kcal/mol), IC50 (nM), and IC50 fold change with respect to unmutated BCR-ABL1 (FCIC50) for dasatinib, AP23534, and PHA739358 in complex with BCR-ABL1 and some single/double mutant isoforms. BCR-ABL1 isoform DASATINIB AP24534 PHA739358 DGbind IC50 FC IC50 DGbind IC50 FC IC50 DGbind IC50 FC IC50 Unmutated −12.39 0.80 – 0.52 −12.67 – 18 −10.6 – T315I −6.44 19000 23750 7.4 −11.1 14 7 −11.13 0.39 V299L −8.21 960 1200 1.3 −12.13 2.5 42 −10.07 2.3 F317L −9.23 170 212.5 12 −10.81 23 53 −9.93 2.9 E255K −10.77 12.8 16 8.8 −10.99 17 45 −10.03 2.5 Q252H −10.85 11.2 14 0.79 −12.42 1.5 25 −10.38 1.4 Y253H −11.08 7.6 9.5 0.55 −12.64 1.1 20 −10.51 1.1 H396R −11.98 1.7 2.125 1.3 −12.13 2.5 23 −10.42 1.3 F359V −12 1.6 2 0.81 −12.41 1.6 26 −10.35 1.4 M244V −12.22 1.4 1.75 1.1 −12.23 2.1 16 −10.64 0.89 V304D −12.27 1 1.25 0.72 −12.48 1.4 22 −10.45 1.2 T315I/F317L −5.47 970000 1212500 21 −10.48 40 68 −9.78 3.1 T315I/V299L −4.83 290000 362500 10 −10.92 19 50 −9.96 2.7 T315I/V304D −6.02 38000 47500 8.8 −11.01 16 12 −10.81 0.66 V299L/F317L −7.42 3650 4563 18 −10.56 34 109 −9.5 5 V304D/V299L −8.05 1250 1563 2.1 −11.84 4 46 −10.01 2.5 F317L/V304D −9.01 250 313 15 −10.68 29 51 −9.95 2.8 All polymutants are predicted to be highly resistant to dasatinib. AP24534 and PHA739358 are predicted to maintain a notable affinity toward the clinically relevant BCR-ABL1 polymytants T315I/V299L and V299L/F317L. Figure 1 depicts dasatinib and AP24534 in complex with the double mutant BCR-ABL1T315I/V299L, as extracted from the corresponding equilibrated molecular dynamics (MD) simulations performed in this study. AP24534 accommodates the great steric hindrance imposed by the polymutant to a much greater extent than dasatinib. BCR-ABL1T315I/V299L results in a dramatic conformational distortion of the entire binding site, leading to a less tight dasatinib binding and lower affinity of the inhibitor for the kinase. Fig.1 MD snapshots of dasatinib (green, left) and AP24534 (orange, right) bound to BCR-ABL1T315I/V299L. The two inhibitors are depicted in stick-and-ball representation, whilst the 3D structure of the kinase is shown as a transparent ribbon. All residues strongly involved in drug binding are highlightedas green/orange colored sticks respectively.The two mutant residues (1315 and L299)are highlighted inlight blue. Note the higher steric clash (light blue areas) in the case of dasatinib, accounting for the very low affinity of the drug for this double mutant. Hydrogenatoms, water molecutes and ions are omitted for clarity. Fig.1. MD snapshots of dasatinib (green, left) and AP24534 (orange, right) bound to BCR-ABL1T315I/V299L. The two inhibitors are depicted in stick-and-ball representation, whilst the 3D structure of the kinase is shown as a transparent ribbon. All residues strongly involved in drug binding are highlightedas green/orange colored sticks respectively.The two mutant residues (1315 and L299)are highlighted inlight blue. Note the higher steric clash (light blue areas) in the case of dasatinib, accounting for the very low affinity of the drug for this double mutant. Hydrogenatoms, water molecutes and ions are omitted for clarity. In conclusion, mutational analysis of patients failing imatinib reveals a high rate of dasatinib resistant polymutants that explain, at least in part, why only ~40% of pts carrying unmutated BCR-ABL1 by direct sequencing achieve CCyR with second generation TKIs. AP24534 and PHA739358 are highly active against these complex polymutants in silico. Preliminary clinical data with these compounds against T315I appear to validate our modeling. Full modeling data for the most prevalent polymutants in complex with a panel of novel TKIs will be presented. Disclosures: Kantarjian: Bristol Myers Squibb: Research Funding; ARIAD: Research Funding; Nerviano: Research Funding. Cortes:Bristol Myers Squibb: Research Funding; ARIAD: Research Funding; Nerviano: Research Funding.

scholarly journals Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption

2021 ◽  
Author(s):  
Wenlin Ren ◽  
Jun Lan ◽  
Xiaohui Ju ◽  
Mingli Gong ◽  
Quanxin Long ◽  
...  
Keyword(s):  
The Netherlands ◽  
Active Surveillance ◽  
Functional Properties ◽  
Genetic Variant ◽  
Vaccine Development ◽  
Binding Mode ◽  
Spike Protein ◽  
Adaptive Mutation ◽  
Steric Clash ◽  
Initial Transmission

COVID-19 patients transmitted SARS-CoV-2 to minks in the Netherlands in April 2020.Subsequently, the mink-associated virus (miSARS-CoV-2) spilled back over into humans.Genetic sequences of the miSARS-CoV-2 identified a new genetic variant known as "Cluster 5" that contained mutations in the spike protein. However, the functional properties of these "Cluster 5" mutations have not been well established. In this study, we found that the Y453F mutation located in the RBD domain of miSARS-CoV-2 is an adaptive mutation that enhances binding to mink ACE2 and other orthologs of Mustela species without compromising, and even enhancing, its ability to utilize human ACE2 as a receptor for entry.Structural analysis suggested that despite the similarity in the overall binding mode of SARS-CoV-2 RBD to human and mink ACE2, Y34 of mink ACE2 was better suited to interact with a Phe rather than a Tyr at position 453 of the viral RBD due to less steric clash and tighter hydrophobic-driven interaction. Additionally, the Y453F spike exhibited resistance to convalescent serum, posing a risk for vaccine development. Thus, our study suggests that since the initial transmission from humans, SARS-CoV-2 evolved to adapt to the mink host, leading to widespread circulation among minks while still retaining its ability to efficiently utilize human ACE2 for entry, thus allowing for transmission of the miSARS-CoV-2 back into humans. These findings underscore the importance of active surveillance of SARS-CoV-2 evolution in Mustela species and other susceptible hosts in order to prevent future outbreaks.

scholarly journals Steric clashes with bound OMP peptides activate the DegS stress-response protease

2015 ◽  
Vol 112 (11) ◽  
pp. 3326-3331 ◽  
Author(s):  
Anna K. de Regt ◽  
Tania A. Baker ◽  
Robert T. Sauer
Keyword(s):  
Outer Membrane Proteins ◽  
Pdz Domain ◽  
Peptide Binding ◽  
Structural Rearrangement ◽  
Signaling Cascade ◽  
Pdz Domains ◽  
Protease Domain ◽  
Allosteric Activation ◽  
Steric Clash ◽  
Envelope Stress

Escherichia coli senses envelope stress using a signaling cascade initiated when DegS cleaves a transmembrane inhibitor of a transcriptional activator for response genes. Each subunit of the DegS trimer contains a protease domain and a PDZ domain. During stress, unassembled outer-membrane proteins (OMPs) accumulate in the periplasm and their C-terminal peptides activate DegS by binding to its PDZ domains. In the absence of stress, autoinhibitory interactions, mediated by the L3 loop, stabilize inactive DegS, but it is not known how this autoinhibition is reversed during activation. Here, we show that OMP peptides initiate a steric clash between the PDZ domain and the L3 loop that results in a structural rearrangement of the loop and breaking of autoinhibitory interactions. Many different L3-loop sequences are compatible with activation but those that relieve the steric clash reduce OMP activation dramatically. Our results provide a compelling molecular mechanism for allosteric activation of DegS by OMP-peptide binding.

scholarly journals Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort

Genes ◽  
2016 ◽  
Vol 7 (11) ◽  
pp. 96 ◽  
Author(s):  
Kyungsoo Ha ◽  
Priya Anand ◽  
Jennifer Lee ◽  
Julie Jones ◽  
Chong Kim ◽  
...  
Keyword(s):  
Genetic Heterogeneity ◽  
Histone Methyltransferase ◽  
Sotos Syndrome ◽  
Set Domain ◽  
Steric Clash ◽  
Brazilian Cohort

scholarly journals Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption

2021 ◽  
Vol 17 (11) ◽  
pp. e1010053
Author(s):  
Wenlin Ren ◽  
Jun Lan ◽  
Xiaohui Ju ◽  
Mingli Gong ◽  
Quanxin Long ◽  
...  
Keyword(s):  
Structural Analysis ◽  
The Netherlands ◽  
Genetic Variant ◽  
Vaccine Development ◽  
Binding Mode ◽  
Spike Protein ◽  
Adaptive Mutation ◽  
Steric Clash ◽  
Genetic Sequences ◽  
Initial Transmission

COVID-19 patients transmitted SARS-CoV-2 to minks in the Netherlands in April 2020. Subsequently, the mink-associated virus (miSARS-CoV-2) spilled back over into humans. Genetic sequences of the miSARS-CoV-2 identified a new genetic variant known as “Cluster 5” that contained mutations in the spike protein. However, the functional properties of these “Cluster 5” mutations have not been well established. In this study, we found that the Y453F mutation located in the RBD domain of miSARS-CoV-2 is an adaptive mutation that enhances binding to mink ACE2 and other orthologs of Mustela species without compromising, and even enhancing, its ability to utilize human ACE2 as a receptor for entry. Structural analysis suggested that despite the similarity in the overall binding mode of SARS-CoV-2 RBD to human and mink ACE2, Y34 of mink ACE2 was better suited to interact with a Phe rather than a Tyr at position 453 of the viral RBD due to less steric clash and tighter hydrophobic-driven interaction. Additionally, the Y453F spike exhibited resistance to convalescent serum, posing a risk for vaccine development. Thus, our study suggests that since the initial transmission from humans, SARS-CoV-2 evolved to adapt to the mink host, leading to widespread circulation among minks while still retaining its ability to efficiently utilize human ACE2 for entry, thus allowing for transmission of the miSARS-CoV-2 back into humans. These findings underscore the importance of active surveillance of SARS-CoV-2 evolution in Mustela species and other susceptible hosts in order to prevent future outbreaks.

Steric clash in real space: biphenyl revisited

2020 ◽  
Vol 22 (37) ◽  
pp. 21251-21256 ◽  
Author(s):  
Rubén Laplaza ◽  
Roberto A. Boto ◽  
Julia Contreras-García ◽  
M. Merced Montero-Campillo
Keyword(s):  
Real Space ◽  
Steric Repulsion ◽  
Interaction Method ◽  
Steric Clash ◽  
Covalent Interaction ◽  
Repulsive Interactions

Long-term discrepancies regarding the origin of steric repulsion in biphenyl are reconciled under the NCI (Non Covalent Interaction) method, reflecting the balance between attractive and repulsive interactions in real space.

Electronically Induced Steric Clash: Synthesis of NMe2-Modified β-Diketiminate-Supported Boron Difluoride Compounds

2020 ◽  
Vol 73 (12) ◽  
pp. 1219
Author(s):  
Balasubramanian Murugesapandian ◽  
Rakesh Ganguly ◽  
Peter T. K. Lee ◽  
Milena Petković ◽  
Jason A. C. Clyburne ◽  
...  
Keyword(s):  
Solid State ◽  
Lone Pair ◽  
Structural Features ◽  
Electron Delocalization ◽  
Central Ring ◽  
Steric Clash ◽  
Boron Difluoride ◽  
Theoretical Analyses

We report on the synthesis and structural features of NMe2-modified β-diketiminate-supported boron difluoride compounds (LArBF2: LAr=[HC(NAr)2(CNMe2)2]–; LPh: Ar=Ph; LTol: Ar=p-tolyl; LXyl: Ar=m-xylyl). The title compounds were prepared in moderate yields (~65%) by insitu deprotonation of the corresponding ligands LArH using KH, followed by the addition of BF3OEt2. According to solid-state and theoretical analyses of the BF2 compounds, the lone pair at each NMe2 group is involved in electron delocalization within the central BC3N2 ring. As a result, the N-aryl substituents sterically clash with the NMe2 groups, causing this central ring to pucker. Several attempts were made to prepare heavy analogues (e.g. LArBX2, X=Cl, Br, I) but only unidentifiable product mixtures were observed. It appears that the observed steric clash between the N-aryl substituents and the NMe2 groups prevented the formation of these heavy analogues.

scholarly journals Cbln1 Is Essential for Interaction-Dependent Secretion of Cbln3

2006 ◽  
Vol 26 (24) ◽  
pp. 9327-9337 ◽  
Author(s):  
Dashi Bao ◽  
Zhen Pang ◽  
Marc A. Morgan ◽  
Jennifer Parris ◽  
Yongqi Rong ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Glutamate Receptor ◽  
Knockout Mice ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Structure And Function ◽  
Related Protein ◽  
Cerebellar Granule ◽  
Steric Clash ◽  
And Function

ABSTRACT Cbln1 and the orphan glutamate receptor GluRδ2 are pre- and postsynaptic components, respectively, of a novel transneuronal signaling pathway regulating synapse structure and function. We show here that Cbln1 is secreted from cerebellar granule cells in complex with a related protein, Cbln3. However, cbln1- and cbln3-null mice have different phenotypes and cbln1 cbln3 double-null mice have deficits identical to those of cbln1 knockout mice. The basis for these discordant phenotypes is that Cbln1 and Cbln3 reciprocally regulate each other's degradation and secretion such that cbln1-null mice lack both Cbln1 and Cbln3, whereas cbln3-null mice lack Cbln3 but have an approximately sixfold increase in Cbln1. Unlike Cbln1, Cbln3 cannot form homomeric complexes and is secreted only when bound to Cbln1. Structural modeling and mutation analysis reveal that, by constituting a steric clash that is masked upon binding Cbln1 in a “hide-and-run” mechanism of endoplasmic reticulum retention, a single arginine confers the unique properties of Cbln3.

Sign in / Sign up

Export Citation Format

Share Document