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Protein flexibility in docking and surface mapping

Katrina W. Lexa, Heather A. Carlson
2012 Quarterly Reviews of Biophysics (print)  
[PubMed: 15456251] Firth-Clark S, Willems HM, Williams A, Harris W. Generation and selection of novel estrogen receptor ligands using the de novo structure-based design tool, SkelGen.  ...  [PubMed: 19291738] Dunbar JB, Smith RD, Yang CY, Ung PMU, Lexa KW, Khazanov NA, Stuckey JA, Wang S, Carlson HA. CSAR benchmark exercise of 2010: selection of the protein-ligand complexes.  ... 
doi:10.1017/s0033583512000066 pmid:22569329 pmcid:PMC4272345 fatcat:s7voxcdb7zbyrgkt7kedvo3lky

A Structure-Based Model for Predicting Serum Albumin Binding

Katrina W. Lexa, Elena Dolghih, Matthew P. Jacobson, Eugene A. Permyakov
2014 PLoS ONE  
Citation: Lexa KW, Dolghih E, Jacobson MP (2014) A Structure-Based Model for Predicting Serum Albumin Binding. PLoS ONE 9(4): e93323.  ...  Predicted ADME properties, including QPlogP o/w and QPlogK hsa , were generated with QikProp 3.3 [44] .  ...  the ''strict set'', using the combined score = 25.41+ a*XPscore+b*QPlogP o/w , where a = 21.95 and b = 7.68.  ... 
doi:10.1371/journal.pone.0093323 pmid:24691448 pmcid:PMC3972100 fatcat:5edyt5sb5jcqbg74awxaflqpwy

Binding to the open conformation of HIV-1 protease

Katrina W. Lexa, Heather A. Carlson
2011 Proteins: Structure, Function, and Bioinformatics  
A recent crystal structure of HIV-1 protease (HIVp) was the first to experimentally observe a ligand targeting an open-flap conformation. Researchers studying a symmetric pyrrolidine inhibitor found that two ligands co-crystallized with the protease, forcing an unusual configuration and unique crystallographic contacts. One molecule is centered in the traditional binding site (α pose), and the other binds between the flaps (β pose). The ligands stack against each other in a region termed the
more » ... e" site. Ligands bound to the eye site should prevent flap closure, but it is unclear if the pyrrolidine inhibitors or the crystal packing are causing the open state. Molecular dynamics simulations were used to examine the solution-state behavior of three possible binding modes: the ternary complex of HIVp+αβ and the binary complexes, HIVp+α and HIVp+β. We show that HIVp+α is the most stable of the three states. During conformational sampling, α takes an asymmetric binding pose, with one naphthyl ring occupying the eye site and the other reoriented down to occupy positions seen with traditional inhibitors. This finding supports previous studies that reveal a requirement for asymmetric binding at the eye site. In fact, if the α pose is modified to splay both naphthyl rings across the binding site like traditional inhibitors, one ring consistently flips to occupy the eye site. Our simulations reveal that interactions to the eye site encourage a conformationally-restrained state, and understanding those contacts may aid the design of ligands to specifically target alternate conformations of the protease.
doi:10.1002/prot.23054 pmid:21604303 pmcid:PMC3124008 fatcat:j6jlvcnuvrddni2i7dycawzuky

Full Protein Flexibility Is Essential for Proper Hot-Spot Mapping

Katrina W. Lexa, Heather A. Carlson
2011 Journal of the American Chemical Society  
The first used the pre-equilibrated 50% w/w mixed solution, providing an even distribution of both solvents (data shown above).  ...  We have also examined 90% and 10% w/w mixed solutions of water and CCN to determine whether maps are more accurate when more or fewer probes are present.  ... 
doi:10.1021/ja1079332 pmid:21158470 pmcid:PMC3081398 fatcat:iaipaqwjjfgd7nlkn7wq7f5jsq

Improving Protocols for Protein Mapping through Proper Comparison to Crystallography Data

Katrina W. Lexa, Heather A. Carlson
2013 Journal of Chemical Information and Modeling  
MixMD data combined for the last 5 ns of 5 individual 50-ns runs of fully flexible HEWL in 50% w/w IPA and water.  ...  MixMD data combined for the last 5 ns for 5 individual 50-ns runs of fully flexible p53 core in 50% w/w IPA and water.  ... 
doi:10.1021/ci300430v pmid:23327200 pmcid:PMC3581705 fatcat:fuo5j34mt5f6jdfdwa4yga24ie

Parameter Choice Matters: Validating Probe Parameters for Use in Mixed-Solvent Simulations

Katrina W. Lexa, Garrett B. Goh, Heather A. Carlson
2014 Journal of Chemical Information and Modeling  
w by probe.  ...  w probe and water.  ... 
doi:10.1021/ci400741u pmid:25058662 pmcid:PMC4144759 fatcat:ija2xcsnmbhvvktueprsetqxz4

Immune factor of bacterial origin protects ticks against host microbial commensals [article]

Beth M Hayes, Atanas D Radkov, Fauna Yarza, Sebastian Flores, Jungyun Rachel Kim, Ziyi Zhao, Katrina W Lexa, Liron Marnin, Jacob Biboy, Victoria Bowcutt, Waldemar Vollmer, Joao HF Pedra (+1 others)
2020 bioRxiv   pre-print
Hard ticks interface with diverse microbes while feeding on vertebrate hosts. We previously discovered that ticks horizontally acquired an antimicrobial toxin gene from bacteria known as domesticated amidase effector 2 (dae2). Here we show that this effector from the tick disease vector Ixodes scapularis (Dae2Is) is delivered to the host bite site via saliva and that its structural and biochemical divergence from bacterial homologs results in an expanded targeting range to include host skin
more » ... obes. Upon disruption of dae2Is, we found higher loads of skin-associated staphylococci within ticks, adversely affecting their fitness. In contrast, Dae2Is has no intrinsic lytic activity against Borrelia burgdorferi, the tick-borne pathogen of Lyme disease. Our observations suggest ticks have evolved to preferentially resist opportunistic pathogens, such as host skin commensals, while tolerating their own symbionts. These results highlight a unique interkingdom interface between blood-feeding vectors, hosts, and their associated microbes where incompatible host-microbe interactions lead to disease.
doi:10.1101/2020.04.10.036376 fatcat:ib33csgtbbf2dpea3yvzpswhn4

Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products

Christopher L Ahlbach, Katrina W Lexa, Andrew T Bockus, Valerie Chen, Phillip Crews, Matthew P Jacobson, R Scott Lokey
2015 Future Medicinal Chemistry  
c/w of 4.02.  ...  The LogPm c/w demonstrated a strong capacity for discriminating between permeable and nonpermeable compounds ( Figure 2A When we calculated the linear correlation between the logPe and the LogPm c/w  ... 
doi:10.4155/fmc.15.78 pmid:26067057 pmcid:PMC5186412 fatcat:46tn7krobzc7vdurkg7xkev7ty

Clarifying allosteric control of flap conformations in the 1TW7 crystal structure of HIV-1 protease

Katrina W. Lexa, Kelly L. Damm, Jerome J. Quintero, Jason E. Gestwicki, Heather A. Carlson
2009 Proteins: Structure, Function, and Bioinformatics  
doi:10.1002/prot.22195 pmid:18704936 pmcid:PMC2635929 fatcat:k2qrepj72vdafk6wi6yduje76y

Identifying binding hot spots on protein surfaces by mixed-solvent molecular dynamics: HIV-1 protease as a test case

Peter M. U. Ung, Phani Ghanakota, Sarah E. Graham, Katrina W. Lexa, Heather A. Carlson, J. McCammon
2015 Biopolymers  
We used three probe-water solutions (acetonitrile-water, isopropanol-water, and pyrimidine-water), first at 50% w/w concentration and later at 5% v/v.  ...  SUPPLEMENTARY MATERIAL Tables report the ratio of probes to water in the 50% w/w and 5% v/v solution environments. Eigenvector data are given.  ...  PMUU is grateful for receiving fellowships from Fred W. Lyons and the University of Michigan Regents.  ... 
doi:10.1002/bip.22742 pmid:26385317 pmcid:PMC4623995 fatcat:xswfm7gm3ngwfbafmtzwistvru

Ramachandran-type plots for glycosidic linkages: Examples from molecular dynamic simulations using the Glycam06 force field

Amanda M. Salisburg, Ashley L. Deline, Katrina W. Lexa, George C. Shields, Karl N. Kirschner
2009 Journal of Computational Chemistry  
can be defined by (a, /, w, x) and (b, /, w, x).  ...  Considering two-bond glycosidic linkages, there are 18 possible conformational regions that can be defined by (a, /, w) and (b, /, w), whereas for three-bond linkages, there are 54 possible regions that  ...  can be defined by (a, /, w, x) and (b, /, w, x).  ... 
doi:10.1002/jcc.21099 pmid:18785152 fatcat:pity4npz2feazhy7hrek2pn7de

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions

Yining Ji, Hongming Li, Alan M. Hyde, Qinghao Chen, Kevin M. Belyk, Katrina W. Lexa, Jingjun Yin, Edward C. Sherer, R. Thomas Williamson, Andrew Brunskill, Sumei Ren, Louis-Charles Campeau (+2 others)
2017 Chemical Science  
Detailed mechanistic studies of a Pd-catalyzed asymmetric C–N coupling led to a rational design of a new series of bis-phosphine mono-oxides ligated Pd(ii) pre-catalysts that allow for reliable and complete catalyst activation.
doi:10.1039/c6sc05472b pmid:28553522 pmcid:PMC5427683 fatcat:zqsn5s4prrej7ibq2bp3stn6ym

Structure of a Peptidoglycan Amidase Effector Targeted to Gram-Negative Bacteria by the Type VI Secretion System

Seemay Chou, Nhat Khai Bui, Alistair B. Russell, Katrina W. Lexa, Taylor E. Gardiner, Michele LeRoux, Waldemar Vollmer, Joseph D. Mougous
2012 Cell Reports  
The target range of a bacterial secretion system can be defined by effector substrate specificity or by the efficacy of effector delivery. Here, we report the crystal structure of Tse1, a type VI secretion (T6S) bacteriolytic amidase effector from Pseudomonas aeruginosa. Consistent with its role as a toxin, Tse1 has a more accessible active site than related housekeeping enzymes. The activity of Tse1 against isolated peptidoglycan shows its capacity to act broadly against Gram-negative bacteria
more » ... and even certain Gram-positive species. Studies with intact cells indicate that Gram-positive bacteria can remain vulnerable to Tse1 despite cell wall modifications. However, interbacterial competition studies demonstrate that Tse1-dependent lysis is restricted to Gram-negative targets. We propose that the previously observed specificity for T6S against Gramnegative bacteria is a consequence of high local effector concentration achieved by T6S-dependent targeting to its site of action rather than inherent effector substrate specificity.
doi:10.1016/j.celrep.2012.05.016 pmid:22813741 pmcid:PMC3401384 fatcat:pvtqvyo4pbhubdj72lwp2mpuvm

CSAR Benchmark Exercise of 2010: Selection of the Protein–Ligand Complexes

James B. Dunbar, Richard D. Smith, Chao-Yie Yang, Peter Man-Un Ung, Katrina W. Lexa, Nickolay A. Khazanov, Jeanne A. Stuckey, Shaomeng Wang, Heather A. Carlson
2011 Journal of Chemical Information and Modeling  
doi:10.1021/ci200082t pmid:21728306 pmcid:PMC3180202 fatcat:cqd3oezs2bbdrlpz7spd75lxoq

Computational Design and Experimental Discovery of an Antiestrogenic Peptide Derived from α-Fetoprotein

Karl N. Kirschner, Katrina W. Lexa, Amanda M. Salisburg, Katherine A. Alser, Leroy Joseph, Thomas T. Andersen, James A. Bennett, Herbert I. Jacobson, George C. Shields
2007 Journal of the American Chemical Society  
W.; Jacobson, H. I.; Shaye, D. D.; Andersen, T. T. Biochim. Biophys. Acta 1999, 1427, 307-314. | Albany Medical College, Department of Obstetrics, Gynecology, and Reproductive Science.  ... 
doi:10.1021/ja070202w pmid:17441722 pmcid:PMC4272344 fatcat:pd2m77ox7vctphu3xywei5zs3m
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