<?xml version="1.0" encoding="ISO-8859-1"?><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id>1870-249X</journal-id>
<journal-title><![CDATA[Journal of the Mexican Chemical Society]]></journal-title>
<abbrev-journal-title><![CDATA[J. Mex. Chem. Soc]]></abbrev-journal-title>
<issn>1870-249X</issn>
<publisher>
<publisher-name><![CDATA[Sociedad Química de México A.C.]]></publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id>S1870-249X2019000100013</article-id>
<article-id pub-id-type="doi">10.29356/jmcs.v63i1.684</article-id>
<title-group>
<article-title xml:lang="en"><![CDATA[What comparisons of natural and chimeric contacts reveal about inhibition of human cathepsins K, L and S by their prosegments]]></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Martínez-Hernández]]></surname>
<given-names><![CDATA[Juan Carlos]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Serratos]]></surname>
<given-names><![CDATA[Iris N.]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Millán-Pacheco]]></surname>
<given-names><![CDATA[César]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Rojo-Domínguez]]></surname>
<given-names><![CDATA[Arturo]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Padilla-Zúñiga]]></surname>
<given-names><![CDATA[Jaqueline]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
</contrib-group>
<aff id="Af1">
<institution><![CDATA[,Universidad Autónoma Metropolitana Departamento de Química Área de Biofisicoquímica]]></institution>
<addr-line><![CDATA[Iztapalapa ]]></addr-line>
<country>Mexico</country>
</aff>
<aff id="Af2">
<institution><![CDATA[,Universidad Autónoma Metropolitana Departamento de Química Área de Química Inorgánica]]></institution>
<addr-line><![CDATA[Iztapalapa ]]></addr-line>
<country>Mexico</country>
</aff>
<aff id="Af3">
<institution><![CDATA[,Universidad Autónoma del Estado de Morelos Facultad de Farmacia ]]></institution>
<addr-line><![CDATA[ ]]></addr-line>
<country>Mexico</country>
</aff>
<aff id="Af4">
<institution><![CDATA[,Universidad Autónoma Metropolitana Departamento de Ciencias Naturales ]]></institution>
<addr-line><![CDATA[Cuajimalpa ]]></addr-line>
<country>Mexico</country>
</aff>
<pub-date pub-type="pub">
<day>00</day>
<month>03</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="epub">
<day>00</day>
<month>03</month>
<year>2019</year>
</pub-date>
<volume>63</volume>
<numero>1</numero>
<fpage>13</fpage>
<lpage>24</lpage>
<copyright-statement/>
<copyright-year/>
<self-uri xlink:href="http://www.scielo.org.mx/scielo.php?script=sci_arttext&amp;pid=S1870-249X2019000100013&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://www.scielo.org.mx/scielo.php?script=sci_abstract&amp;pid=S1870-249X2019000100013&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://www.scielo.org.mx/scielo.php?script=sci_pdf&amp;pid=S1870-249X2019000100013&amp;lng=en&amp;nrm=iso"></self-uri><abstract abstract-type="short" xml:lang="en"><p><![CDATA[Abstract: Human cathepsins K, L, and S, which are involved in the development of several serious diseases, are strongly inhibited by their related prosegments, to which they are covalently bound or simply forming complexes. In this work, three-dimensional structures of the three natural complexes of these enzymes with their related proregions were constructed, as well as six chimeric complexes of the same three prosegments with their non-cognate enzymes. We made a comparative study of the contacts in all nine structures throughout their active sites. The analysis was performed looking for a structural parameter that could agree with the values of the inhibition constants reported experimentally for each of the nine complexes. We found that this correlating parameter was the difference of the electrostatic energy (involving hydrogen bonds and ion pairs) at the binding interface of a 13-amino acid fragment of the prosegments. We used the results of this work, on the one hand, to identify the key residues involved in the electrostatic intermolecular recognition in each studied complex and, on the other, to explain some results achieved by different research groups on the inhibition of the same enzymes analyzed here. It was found that the natural cathepsin L complex showed a higher number of electrostatic interactions, some of them interconnected, when compared to the other two natural complexes. In addition, the chimeric contacts revealed binding sites that could be used to achieve a more potent inhibition of these cathepsins, avoiding cross-interactions.]]></p></abstract>
<abstract abstract-type="short" xml:lang="es"><p><![CDATA[Resumen: Se sabe que las catepsinas humanas K, L y S, involucradas en el desarrollo de diversas enfermedades graves, son fuertemente inhibidas por sus prosegmentos cognados, a los que se unen covalentemente o sólo formando complejos. En este trabajo se construyeron las estructuras tridimensionales de los tres complejos naturales de estas enzimas, con sus prorregiones cognadas, así como seis complejos quiméricos de los mismos tres prosegmentos con enzimas no cognadas. Todo lo anterior se cumplió para llevar a cabo un estudio comparativo de los contactos estructurales de la interfaz a lo largo del sitio activo enzimático en los complejos construidos. El análisis implicó la búsqueda de un parámetro estructural que correlacionara con las constantes de inhibición reportadas experimentalmente para los nueve complejos estudiados. Se encontró que este parámetro fue la diferencia de energía electrostática (debida a enlaces de hidrógeno y pares iónicos) en la unión al sitio activo de un fragmento de 13 aminoácidos de los prosegmentos. Usamos los resultados de este trabajo, por una parte, para identificar los residuos clave involucrados en el reconocimiento intermolecular en cada complejo estudiado y, por otra, para explicar algunos datos reportados por diferentes grupos de investigación sobre la inhibición de las mismas enzimas aquí analizadas. Se encontró que el complejo natural de catepsina L establece un mayor número de interacciones electrostáticas, algunas de ellas altamente interconectadas, en comparación con los otros dos complejos naturales. Además, los contactos quiméricos revelaron sitios de unión que podrían usarse para lograr una inhibición más potente de estas catepsinas, evitando interacciones cruzadas.]]></p></abstract>
<kwd-group>
<kwd lng="en"><![CDATA[human cathepsins]]></kwd>
<kwd lng="en"><![CDATA[cathepsin inhibition]]></kwd>
<kwd lng="en"><![CDATA[proteinase chimeric complexes]]></kwd>
<kwd lng="en"><![CDATA[protease prosegments]]></kwd>
<kwd lng="en"><![CDATA[cysteine proteases]]></kwd>
<kwd lng="es"><![CDATA[catepsinas humanas]]></kwd>
<kwd lng="es"><![CDATA[inhibición de catepsinas]]></kwd>
<kwd lng="es"><![CDATA[complejos proteínicos quiméricos]]></kwd>
<kwd lng="es"><![CDATA[prosegmentos de proteasas]]></kwd>
<kwd lng="es"><![CDATA[proteasas cisteínicas]]></kwd>
</kwd-group>
</article-meta>
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