Victor M. Garsky
United States Military Academy
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Featured researches published by Victor M. Garsky.
Journal of Biological Chemistry | 1996
Hilary B. Schock; Victor M. Garsky; Lawrence C. Kuo
Site-specific substitutions of as few as four amino acids (M46I/L63P/V82T/I84V) of the human immunodeficiency virus type 1 (HIV-1) protease engenders cross-resistance to a panel of protease inhibitors that are either in clinical trials or have recently been approved for HIV therapy (Condra, J. H., Schleif, W. A., Blahy, O. M., Gadryelski, L. J., Graham, D. J., Quintero, J. C., Rhodes, A., Robbins, H. L., Roth, E., Shivaprakash, M., Titus, D., Yang, T., Teppler, H., Squires, K. E., Deutsch, P. J., and Emini, E. A. (1995) Nature374, 569-571). These four substitutions are among the prominent mutations found in primary HIV isolates obtained from patients undergoing therapy with several protease inhibitors. Two of these mutations (V82T/I84V) are located in, while the other two (M46I/L63P) are away from, the binding cleft of the enzyme. The functional role of these mutations has now been delineated in terms of their influence on the binding affinity and catalytic efficiency of the protease. We have found that the double substitutions of M46I and L63P do not affect binding but instead endow the enzyme with a catalytic efficiency significantly exceeding (110-360%) that of the wild-type enzyme. In contrast, the double substitutions of V82T and I84V are detrimental to the ability of the protease to bind and, thereby, to catalyze. When combined, the four amino acid replacements institute in the protease resistance against inhibitors and a significantly higher catalytic activity than one containing only mutations in its active site. The results suggest that in raising drug resistance, these four site-specific mutations of the protease are compensatory in function; those in the active site diminish equilibrium binding (by increasing Ki), and those away from the active site enhance catalysis (by increasing kcat/KM). This conclusion is further supported by energy estimates in that the Gibbs free energies of binding and catalysis for the quadruple mutant are quantitatively dictated by those of the double mutants.
British Journal of Pharmacology | 2010
Jerzy Karczewski; Robert H. Spencer; Victor M. Garsky; Annie Liang; Michael Leitl; Matthew J. Cato; Sean P. Cook; Stefanie A. Kane; Mark O. Urban
BACKGROUND AND PURPOSE Inflammatory pain is triggered by activation of pathways leading to the release of mediators such as bradykinin, prostaglandins, interleukins, ATP, growth factors and protons that sensitize peripheral nociceptors. The activation of acid‐sensitive ion channels (ASICs) may have particular relevance in the development and maintenance of inflammatory pain. ASIC3 is of particular interest due to its restricted tissue distribution in the nociceptive primary afferent fibres and its high sensitivity to protons.
Virology | 2009
Tong-Ming Fu; Daniel C. Freed; Melanie Horton; Jiang Fan; Michael Citron; Joseph G. Joyce; Victor M. Garsky; Danilo R. Casimiro; Qinjian Zhao; John W. Shiver; Xiaoping Liang
M2 protein of influenza A virus has been implicated as a target for vaccines with broad cross-strain coverage. Studies in small animal models have shown that antibody responses induced by 23-mer M2 peptide vaccines can provide protection against influenza A virus challenge. To study antiviral mechanisms of Merck M2-OMPC conjugate vaccine, we generated and characterized four M2 peptide-specific monoclonal antibodies (mAbs). Here we demonstrated that the protection by our M2 mAbs is independent of NK-mediated effector functions in mice. The protective mAbs preferentially bind to M2 multimers composed of two or more M2 peptides in parallel orientation. Our findings indicate that the protective M2 Ab prefer to bind to epitopes located within the N-terminal 10 amino acids of the M2 peptide, and the epitopes are likely formed by two M2 peptides in parallel orientation. The implications of these results in antiviral mechanisms of immune responses induced by M2 vaccines are discussed.
Journal of Biomolecular NMR | 1994
Yuan Chen; Asif K. Suri; Dorothea Kominos; Gautam Sanyal; Adel M. Naylor; Steven M. Pitzenberger; Victor M. Garsky; Ronald M. Levy; Jean Baum
SummaryThe snake venom protein echistatin contains the cell recognition sequence Arg-Gly-Asp and is a potent inhibitor of platelet aggregation. The three-dimensional structure of echistatin and the dynamics of the active RGD site are presented. A set of structures was determined using the Distance Geometry method and subsequently refined by Molecular Dynamics and energy minimization. Disulfide pairings are suggested, based on violations of experimental constraints. The structures satisfy 230 interresidue distance constraints, derived from nuclear Overhauser effect measurements, five hydrogen-bonding constraints, and 21 torsional constraints from vicinal spin-spin coupling constants. The segment from Gly5 to Cys20 and from Asp30 to Asn42 has a well-defined conformation and the Arg-Gly-Asp sequence, which adopts a turn-like structure, is located at the apex of a nine-residue loop connecting the two strands of a distorted β-sheet. The mobility of the Arg-Gly-Asp site has been quantitatively characterized by 15N relaxation measurements. The overall correlation time of echistatin was determined from fluorescence measurements, and was used in a model-free analysis to determine internal motional parameters. The active site has order parameters of 0.3–0.5, i.e., among the smallest values ever observed at the active site of a protein. Correlation of the flexible region of the protein as characterized by relaxation experiments and the NMR solution structures was made by calculating generalized order parameters from the ensemble of three-dimensional structures. The motion of the RGD site detected experimentally is more extensive than a simple RGD loop ‘wagging’ motional model, suggested by an examination of superposed solution structures.
Bioorganic & Medicinal Chemistry Letters | 1992
Linda L. Chang; John Hannah; Wallace T. Ashton; Gary H. Rasmusson; T.J. Ikeler; Gool F. Patel; Victor M. Garsky; C. Uncapher; G. Yamanaka; W.L. McClements; Richard L. Tolman
Abstract Structural modifications of the Tyr, Asn, and Leu residues of YVVNDL, a peptide which is equipotent to YAGAVVNDL in the inhibition of herpes simplex virus type 2 ribonucleotide reductase (HSV-2 RR), have produced peptides which are as much as 90- to 120-times as potent as YAGAVVNDL in vitro against HSV-2 RR. The chemistry and the structure activity relationships of these inhibitors are described. For the inhibition of herpes simplex virus type 2 ribonucleotide reductase (HSV-2 RR), structure-activity relationship studies on Y, N, and/or L of YVVNDL (equipotent to YAGAVVNDL on HSV-2 RR) using synthetic peptides are reported. The most potent of these, YVV-N(Nγ-Me2)-D-L(γ-Me), and (Bzl)2CHCO-VVND-L(γ-Me) had relative potencies of 110 and 120, respectively, relative to YAGAVVNDL.
Journal of Biological Chemistry | 1998
Shi-Shan Mao; Craig T. Przysiecki; Julie A. Krueger; Carolyn M. Cooper; Lewis Sd; Joseph G. Joyce; Colin Lellis; Victor M. Garsky; Mohinder K. Sardana; Jules A. Shafer
Studies of antistasin, a potent factor Xa inhibitor with anticoagulant properties, were performed wherein the properties of the full-length antistasin polypeptide (ATS-119) were compared with the properties of forms of antistasin truncated at residue 116 (ATS-116) and residue 112 (ATS-112). ATS-119 was 40-fold more potent than ATS-112 in prolonging the activated partial thromboplastin time (APTT), whereas ATS-119 inhibited factor Xa 2.2-fold less avidly and about 5-fold more slowly than did ATS-112. The decreased reactivity of ATS-119 suggests that the carboxyl-terminal domain of ATS-119 stabilizes an ATS conformation with a reduced reactivity toward factor Xa. The observation that calcium ion increases the reactivity of ATS-119 but not that of ATS-112 suggests that calcium ion may disrupt interactions involving the carboxyl terminus of ATS-119. Interestingly, ATS-119 inhibited factor Xa in the prothrombinase complex 2–6-fold more potently and 2–3-fold faster than ATS-112. These differences in affinity and reactivity might well account for the greater effectiveness of ATS-119 in prolonging the APTT and suggest that the carboxyl-terminal domain of ATS-119 disrupts interactions involving phospholipid, factor Va, and prothrombin in the prothrombinase complex. The peptide RPKRKLIPRLS, corresponding to the carboxyl domain of ATS-119 prolonged the APTT and inhibited prothrombinase-catalyzed processing of prothrombin, but it failed to inhibit the catalytic activity of isolated factor Xa. Thus, this novel inhibitor appears to exert its inhibitory effects at a site removed from the active site of factor Xa.
Annals of the New York Academy of Sciences | 1998
Russell J. Mortishire-Smith; Howard B. Broughton; Victor M. Garsky; Ernest J. Mayer; Robert G. Johnson
ABSTRACT: The cardiac sarcoplasmic reticulum (SR) protein phospholamban (PLB) is an endogenous inhibitor of the SR Ca2+‐ATPase. Phosphorylation of PLB relieves this inhibition and up‐regulates calcium transport. PLB has proved remarkably difficult to study by conventional solution‐state nuclear magnetic resonance (NMR) methods, due primarily to the extreme hydrophobic nature of the protein and its propensity to form pentamers. That the C‐terminal domain of PLB is helical and membrane spanning is now well established; the structure of the cytoplasmic domain is relatively ill defined. In order to discern the effect of phosphorylation on the structure of the cytoplasmic domain, we have characterized a variety of model peptides in several structure‐inducing and/or lipid‐mimicking environments using circular dichroism and solution‐state NMR. The resolution of peptide structures obtained in aqueous trifluoroethanol was markedly improved by the incorporation of 15 N labels into the peptide backbone, allowing a variety of isotope edited, filtered, and resolved techniques to be applied. Molecular dynamics simulations on the full‐length protein were combined with an analysis of published data to suggest a revised model for the structure of PLB.
Vaccine | 2004
Jiang Fan; Xiaoping Liang; Melanie Horton; Helen C. Perry; Michael Citron; Gwen J Heidecker; Tong-Ming Fu; Joseph G. Joyce; Craig T. Przysiecki; Paul M. Keller; Victor M. Garsky; Roxana Ionescu; Yvette Rippeon; Li Shi; Michael Chastain; Jon H. Condra; Mary-Ellen Davies; Jason J. Z. Liao; Emilio A. Emini; John W. Shiver
Journal of Biological Chemistry | 2001
Xiao-Ping Shi; Elizabeth Chen; Kuo-Chang Yin; Sang Na; Victor M. Garsky; Ming-Tain Lai; Yue-Ming Li; Michael Platchek; R. Bruce Register; Mohinder K. Sardana; Mei-Jy Tang; James Thiebeau; Theresa Wood; Jules A. Shafer; Stephen J. Gardell
Journal of Biological Chemistry | 2002
Joseph G. Joyce; William Hurni; Michael J. Bogusky; Victor M. Garsky; Xiaoping Liang; Michael Citron; Renee Danzeisen; Michael D. Miller; John W. Shiver; Paul M. Keller