{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T19:21:28Z","timestamp":1787253688696,"version":"build-2736575974"},"reference-count":41,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,1,1]]},"abstract":"<jats:p>Obtustatin and viperistatin represent the shortest known snake venom monomeric disintegrins. In the present study, we have produced recombinant full-length wild-type and site-directed mutants of obtustatin to assess the role of the K21TS23 tripeptide and C-terminal residues for specific inhibition of the \u03b11\u03b21 integrin. Thr22 appeared to be the most critical residue for disintegrin activity, whereas substitution of the flanking lysine or serine residues for alanine resulted in a less pronounced decrease in the anti-\u03b11\u03b21 integrin activity of the disintegrin. The triple mutant A21AA23 was devoid of blocking activity towards \u03b11\u03b21 integrin-mediated cell adhesion. The potency of recombinant KTS-disintegrins also depended on the residue C-terminally adjacent to the active motif. Substitution of Leu24 of wild-type obtustatin for an alanine residue slightly decreased the inhibitory activity of the mutant, whereas an arginine residue in this position enhanced the potency of the mutant over wild-type obtustatin by 6-fold. In addition, the replacements L38V and P40Q may account for a further 25-fold increase in \u03b11\u03b21 inhibitory potency of viperistatin over KTSR-obtustatin.<\/jats:p>","DOI":"10.1042\/bj20081403","type":"journal-article","created":{"date-parts":[[2008,9,10]],"date-time":"2008-09-10T11:55:21Z","timestamp":1221047721000},"page":"95-101","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Structural requirements of KTS-disintegrins for inhibition of \u03b11\u03b21 integrin"],"prefix":"10.1042","volume":"417","author":[{"given":"Meghan\u00a0C.","family":"Brown","sequence":"first","affiliation":[{"name":"Department of Biology, Center for Neurovirology, Temple University School of Medicine, Phildelphia, PA 19122, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes\u00a0A.","family":"Eble","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Department of Vascular Matrix Biology, Frankfurt University Hospital, 60590 Frankfurt-am-Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan\u00a0J.","family":"Calvete","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Valencia, C.S.I.C., Valencia 46010, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezary","family":"Marcinkiewicz","sequence":"additional","affiliation":[{"name":"Department of Biology, Center for Neurovirology, Temple University School of Medicine, Phildelphia, PA 19122, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2008,12,12]]},"reference":[{"key":"2021112214283778200_B1","first-page":"29","article-title":"Platelet integrin GPIIb\/IIIa: structure\u2013function correlations. An update and lessons from other integrins","volume":"222","author":"Calvete","year":"1999","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"2021112214283778200_B2","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0092-8674(02)00971-6","article-title":"Integrins: bidirectional, allosteric signaling machines","volume":"110","author":"Hynes","year":"2002","journal-title":"Cell"},{"key":"2021112214283778200_B3","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1034\/j.1600-065X.2002.18613.x","article-title":"Integrin activation and structural rearrangement","volume":"186","author":"Takagi","year":"2002","journal-title":"Immunol. Rev."},{"key":"2021112214283778200_B4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1002\/jcp.21237","article-title":"Cell-matrix adhesion","volume":"213","author":"Berrier","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"2021112214283778200_B5","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev.immunol.25.022106.141618","article-title":"Structural basis of integrin regulation and signaling","volume":"25","author":"Luo","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2021112214283778200_B6","doi-asserted-by":"crossref","first-page":"867","DOI":"10.2174\/1381612053381738","article-title":"Collagen-binding integrins as pharmaceutical targets","volume":"11","author":"Eble","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"2021112214283778200_B7","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2174\/138945008783502494","article-title":"Collagen receptor integrins: rising to the challenge","volume":"9","author":"McCall","year":"2008","journal-title":"Curr. Drug Targets"},{"key":"2021112214283778200_B8","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s002390010134","article-title":"Evolution of the integrin \u03b1 and \u03b2 families","volume":"52","author":"Hughes","year":"2001","journal-title":"J. Mol. Evol."},{"key":"2021112214283778200_B9","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1042\/bst0270826","article-title":"Integrin I domains and their function","volume":"27","author":"Leitinger","year":"1999","journal-title":"Biochem. Soc. Trans."},{"key":"2021112214283778200_B10","doi-asserted-by":"crossref","first-page":"32182","DOI":"10.1074\/jbc.274.45.32182","article-title":"Determinants of ligand binding specificity of the \u03b11\u03b21 and \u03b12\u03b21 integrins","volume":"274","author":"Dickeson","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112214283778200_B11","first-page":"2020","article-title":"Obtustatin: a potent selective inhibitor of \u03b11\u03b21 integrin in vitro and angiogenesis in vivo","volume":"63","author":"Marcinkiewicz","year":"2003","journal-title":"Cancer Res."},{"key":"2021112214283778200_B12","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.febslet.2004.10.050","article-title":"Structural determinants of the selectivity of KTS-disintegrins for the \u03b11\u03b21 integrin","volume":"577","author":"Kisiel","year":"2004","journal-title":"FEBS Lett."},{"key":"2021112214283778200_B13","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.2174\/138161207782023766","article-title":"KTS and RTS-disintegrins: anti-angiogenic viper venom peptides specifically targeting the \u03b11\u03b21 integrin","volume":"13","author":"Calvete","year":"2007","journal-title":"Curr. Pharm. Des."},{"key":"2021112214283778200_B14","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1042\/BJ20051678","article-title":"Molecular cloning of disintegrins from Cerastes vipera and Macrovipera lebetina transmediterranea venom gland cDNA libraries: insight into the evolution of the snake venom integrin-inhibition system","volume":"395","author":"Sanz","year":"2006","journal-title":"Biochem. J."},{"key":"2021112214283778200_B15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxicon.2004.07.028","article-title":"Molecular diversity and accelerated evolution of C-type lectin-like proteins from snake venom","volume":"45","author":"Ogawa","year":"2005","journal-title":"Toxicon"},{"key":"2021112214283778200_B16","first-page":"289","article-title":"Disintegrins and other naturally occurring antagonists of platelet fibrinogen receptors","volume":"31","author":"Niewiarowski","year":"1994","journal-title":"Semin. Hematol."},{"key":"2021112214283778200_B17","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2174\/1381612053381765","article-title":"Functional characteristic of snake venom disintegrins: potential therapeutic implication","volume":"11","author":"Marcinkiewicz","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"2021112214283778200_B18","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.toxicon.2005.02.024","article-title":"Snake venom disintegrins: evolution of structure and function","volume":"45","author":"Calvete","year":"2005","journal-title":"Toxicon"},{"key":"2021112214283778200_B19","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1007\/s00018-006-6315-0","article-title":"Snake venom components and their applications in biomedicine","volume":"63","author":"Koh","year":"2006","journal-title":"Cell. Mol. Life Sci."},{"key":"2021112214283778200_B20","doi-asserted-by":"crossref","first-page":"9359","DOI":"10.1016\/S0021-9258(18)92826-7","article-title":"Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri","volume":"266","author":"Scarborough","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2021112214283778200_B21","doi-asserted-by":"crossref","first-page":"13302","DOI":"10.1021\/bi9906930","article-title":"Structural and functional characterization of EMF10, a heterodimeric disintegrin from Eristocophis macmahoni venom that selectively inhibits \u03b15\u03b21 integrin","volume":"38","author":"Marcinkiewicz","year":"1999","journal-title":"Biochemistry"},{"key":"2021112214283778200_B22","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1021\/bi015627o","article-title":"The presence of the WGD motif in CC8 heterodimeric disintegrin increases its inhibitory effect on \u03b1IIb\u03b23, \u03b1v\u03b23, and \u03b15\u03b21 integrins","volume":"41","author":"Calvete","year":"2002","journal-title":"Biochemistry"},{"key":"2021112214283778200_B23","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1110\/ps.0230203","article-title":"Amino acid sequence and homology modeling of obtustatin, a novel non-RGD-containing short disintegrin isolated from the venom of Vipera lebetina obtusa","volume":"12","author":"Moreno-Murciano","year":"2003","journal-title":"Protein Sci."},{"key":"2021112214283778200_B24","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1002\/ijc.23777","article-title":"Angiostatic activity of obtustatin as \u03b11\u03b21 integrin inhibitor in experimental melanoma growth","volume":"123","author":"Brown,\u00a0M.\u00a0C.","year":"2008","journal-title":"Int. J. Cancer"},{"key":"2021112214283778200_B25","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1002\/pmic.200402024","article-title":"Snake venomics: comparative analysis of the venom proteomes of the Tunisian snakes Cerastes cerastes, Cerastes vipera and Macrovipera lebetina","volume":"5","author":"Bazaa","year":"2005","journal-title":"Proteomics"},{"key":"2021112214283778200_B26","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1038\/labinvest.3700350","article-title":"Lebestatin, a disintegrin from Macrovipera venom, inhibits integrin-mediated cell adhesion, migration and angiogenesis","volume":"85","author":"Olfa","year":"2005","journal-title":"Lab. Invest."},{"key":"2021112214283778200_B27","doi-asserted-by":"crossref","first-page":"40714","DOI":"10.1074\/jbc.M509738200","article-title":"cDNA cloning and functional expression of jerdostatin, a novel RTS-disintegrin from Trimeresurus jerdonii and a specific antagonist of the \u03b11\u03b21 integrin","volume":"280","author":"Sanz","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112214283778200_B28","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0022-2836(03)00371-1","article-title":"NMR solution structure of the non-RGD disintegrin obtustatin","volume":"329","author":"Moreno-Murciano","year":"2003","journal-title":"J. Mol. Biol."},{"key":"2021112214283778200_B29","doi-asserted-by":"crossref","first-page":"45570","DOI":"10.1074\/jbc.M307030200","article-title":"Concerted motions of the integrin-binding loop and the C-terminal tail of the non-RGD disintegrin obtustatin","volume":"278","author":"Monle\u00f3n","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112214283778200_B30","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1021\/bi035853t","article-title":"Structural requirements of MLD-containing disintegrins for functional interaction with \u03b14\u03b21 and \u03b19\u03b21 integrins","volume":"43","author":"Bazan-Socha","year":"2004","journal-title":"Biochemistry"},{"key":"2021112214283778200_B31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0378-1119(88)90005-4","article-title":"Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase","volume":"67","author":"Smith","year":"1988","journal-title":"Gene"},{"key":"2021112214283778200_B32","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1182\/blood.V90.4.1565","article-title":"Significance of RGD loop and C-terminal domain of echistatin for recognition of \u03b1IIb\u03b23 and \u03b1v\u03b23 integrins and expression of ligand-induced binding site","volume":"90","author":"Marcinkiewicz","year":"1997","journal-title":"Blood"},{"key":"2021112214283778200_B33","doi-asserted-by":"crossref","first-page":"25745","DOI":"10.1074\/jbc.M509942200","article-title":"Collagen XVI harbors an integrin \u03b11\u03b21 recognition site in its C-terminal domains","volume":"281","author":"Eble","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021112214283778200_B34","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1107\/S0907444998003254","article-title":"Crystallography and NMR system: a new software suite for macromolecular structure determination","volume":"54","author":"Brunger","year":"1998","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2021112214283778200_B35"},{"key":"2021112214283778200_B36","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1042\/bst0320407","article-title":"Monoclonal antibodies as probes of integrin priming and activation","volume":"32","author":"Humphries","year":"2004","journal-title":"Biochem. Soc. Trans."},{"key":"2021112214283778200_B37","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1083\/jcb.132.4.717","article-title":"MDC9, a widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains","volume":"132","author":"Weskamp","year":"1996","journal-title":"J. Cell Biol."},{"key":"2021112214283778200_B38","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3109\/13550289509113966","article-title":"Identification of three new JC virus proteins generated by alternative splicing of the early viral mRNA","volume":"1","author":"Trowbridge","year":"1995","journal-title":"J. Neurovirol."},{"key":"2021112214283778200_B39","doi-asserted-by":"crossref","first-page":"20233","DOI":"10.1016\/S0021-9258(17)31981-6","article-title":"Selective recognition of cyclic RGD peptides of NMR defined conformation by \u03b1IIb\u03b23, \u03b1v\u03b23 and \u03b15\u03b21 integrins","volume":"269","author":"Pfaff","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2021112214283778200_B40","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/0014-5793(96)00716-8","article-title":"Importance of the structure of the RGD-containing loop in the disintegrins echistatin and eristostatin for recognition of \u03b1IIb\u03b23 and \u03b1v\u03b23 integrins","volume":"391","author":"McLane","year":"1996","journal-title":"FEBS Lett."},{"key":"2021112214283778200_B41","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1074\/jbc.271.1.289","article-title":"Substitutions of proline 42 to alanine and methionine 46 to asparagine around the RGD domain of the neurotoxin dendroaspin alter its preferential antagonism to that resembling the disintegrin elegantin","volume":"271","author":"Lu","year":"1996","journal-title":"J. Biol. Chem."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/417\/1\/95\/659715\/bj4170095.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/417\/1\/95\/659715\/bj4170095.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T17:57:19Z","timestamp":1637603839000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/417\/1\/95\/45093\/Structural-requirements-of-KTS-disintegrins-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12,12]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,1,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20081403","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,12,12]]}}}