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ПЕТЛИ NGF 

 

А.В.ТАРАСЮК, Н.М.САЗОНОВА, И.О.ЛОГВИНОВ,  

Т.А.АНТИПОВА, Т.А.ГУДАШЕВА 

ФГБНУ «НИИ фармакологии имени В.В. Закусова» 

[e-mail] 

РОССИЙСКАЯ ФЕДЕРАЦИЯ 

 

Фактор роста нервов (NGF), первый из семейства нейротрофинов, со времени открытия в 

начале 50-х  годов XX века  привлекает  внимание  как  возможное  средство  лечения  острых 

нарушений мозгового кровообращения и ряда нейродегенеративных заболеваний. Применение 

NGF  в  клинике  ограничено  серьезными  побочными  эффектами - гиперальгезией  и  потерей 

веса,  а  также  плохими  фармакокинетическими  свойствами.  Поэтому  ведется  активный  поиск 

низкомолекулярных  соединений,  обладающих  эффектами NGF, перспективными  для 

фармакотерапии, но свободных от недостатков полноразмерного белка. 

Ранее [Gudasheva T.A. et al. / J. Biomed. Sci. 2015] был получен активный миметик NGF ГК-

2,  сконструированный  на  основе  наиболее  экспонированной 4-й  петли  нейротрофина, 

обладающий  нейропротекторными  свойствами.  Для  более  детального  изучения  функций 

нейротрофина NGF с  помощью  его  низкомолекулярных  миметиков  были  сконструированы  и 

исследованы миметики 3-й петли NGF. 

Для  дизайна  новых  миметиков  был  выбран  бета-изгиб 3-й  петли,  содержащей  остатки  -

Ser73-Lys74-His75-Trp76-. В структуре миметика сохраняли аминокислотные остатки централь-

ного фрагмента бета-изгиба 3-й петли (-Lys74-His75-), боковые радикалы которых по геометри-

ческим  данным  могут  наиболее  глубоко  проникать  в  зону  связывания  рецептора  и  наиболее 

полно распознаваться. Периферийный остаток -Ser73- был заменен его биоизостером, остатком 

гамма-оксимасляной  кислоты,  а  остаток -Trp76- – амидной  группой.  Цели  этих  двух  замен – 

стабилизация  конформации  бета-изгиба,  увеличение  устойчивости  соединения  к  действию 

пептидаз, а также удешевление синтеза. 

Так  как NGF взаимодействует  с  рецептором  в  гомодимерной  форме,  для  получения 

соединения  с агонистической активностью мы также получили гомодимерную форму из двух 

миметиков бета-изгиба димеризовав их голова-к-голове с помощью гексаметилендиаминового 

спейсера. Таким образом, был сконструирован димерный дипептидный миметик 3-й петли NGF 

ГТС-115 - гексаметилендиамид  бис-(N-гамма-оксибутирил-L-лизил-L-гистидина),  а  также  его 

ацетилсодержащий аналог - ГТС-113 - гексаметилендиамид бис-(N-ацетил-L-лизил-L-гистидина). 

Пептиды  ГТС-113  и  ГТС-115  получали  с  использованием  классических  методов  пептид-

ного синтеза в растворе. Использовали Z/Boc - стратегию защитных групп, наращивание пеп-

тидной  цепи  вели  с N-конца,  конденсацию  аминокислотных  остатков  проводили  методом 

активированных N-оксисукцинимидных  эфиров.  Конденсацию N-защищенного  дипептида  с 

гексаметилендиамином  проводили  азидным  методом.  Целевые  соединения  получали  в  виде 

гидрохлоридов с выходами 46% и 43%. 

С  использованием  культуры  клеток  НТ22  в  условиях  окислительного  стресса,  было 

показано наличие у миметика ГТС-115 нейропротекторной активности в концентрациях от 10-5 

до 10-7М. Ацетилсодержащий миметик ГТC-113 не проявил активности. 

Полученные  результаты  позволяют  сделать  заключение  о  важной  роли  остатка  серина 

(Ser73)  для  проявления  нейропротекторной  активности  миметиком 3-й  петли  нейротрофина 

NGF ГТС-115. 

Работа частично выполнена при поддержке Российского научного фонда (проект № 14-15-

00596). 

 

 

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Qafqaz University                                                                                          29-30 April 2016, Baku, Azerbaijan 

USING Y CHROMOSOMAL HAPLOGROUPS IN GENETIC 

ASSOCIATION STUDIES AND SUGGESTED IMPLICATIONS 

 

Denis A. BAIRD

1  

A. Mesut ERZURUMLUOGLU

2 

1 

School of Clinical Sciences, Musculoskeletal Research Unit,  

Learning and Research Building, Southmead Hospital,  

Bristol, UK. 

2

Genetic Epidemiology Group,  

Department of Health Sciences, University of Leicester,  

Leicester, UK 

[e-mail] 

 

Y chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in 

genetic epidemiology, although associations between Y-DNA haplogroups and several traits 

(including cardio-metabolic traits) have been reported. In apparently homogeneous populations, there 

is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden 

stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, 

we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing 

associations between autosomal SNPs and phenotypes will yield difference in association. For proof of 

concept, we derived Y-DNA haplogroups from 6,537 males from two epidemiological cohorts, 

ALSPAC (N=5,080, 816 Y-DNA SNPs) and 1958 Birth Cohort (N=1,457, 1,849 Y-DNA SNPs). For 

illustration, we studied well-known associations between 32 SNPs and body mass index (BMI), 

including associations involving FTO SNPs. Overall, no association was replicated in both cohorts 

when Y-DNA haplogroups were considered and this suggests that, for BMI at least, there is little 

evidence of differences in phenotype or gene association by Y-DNA structure. Further studies using 

other traits, Phenome-wide association studies (PheWAS), haplogroups and/or autosomal SNPs are 

required to test the generalisability of this approach. 

 

 

 

 

IV INTERNATIONAL SCIENTIFIC CONFERENCE OF YOUNG RESEARCHERS 

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Qafqaz University                                                                                          29-30 April 2016, Baku, Azerbaijan 

IMPORTANCE OF GENETIC STUDIES IN CONSANGUINEOUS 

POPULATIONS FOR THE CHARACTERIZATION OF NOVEL 

HUMAN GENE FUNCTIONS 

 

A. Mesut ERZURUMLUOGLU 

Genetic Epidemiology Group,  

Department of Health Sciences, University of Leicester,  

Leicester, UK 

[e-mail] 

 

Consanguineous offspring have elevated levels of homozygosity. Autozygous stretches within 

their genome are likely toharbour loss of function (LoF) mutations which will lead to complete 

inactivation or dysfunction of genes. Studyingconsanguineous offspring with clinical phenotypes has 

been very useful for identifying disease causal mutations. However,at present, most of the genes in the 

human genome have no disorder associated with them and/or have unknown function. Thisis 

presumably mostly due to the fact that homozygous LoFvariants are not observed in outbred 

populations which are themain focus of large sequencing projects. However, another reason may be 

that many genes in the genome – even whencompletely “knocked out” – do not cause a distinct or 

defined phenotype. In a recently published paper, I discussed the benefits and implicationsof studying 

consanguineous populations, as opposed to the traditional approach of analysing a subset of 

consanguineousfamilies or individuals with disease. I also suggested that studying consanguineous 

populations “as a whole” can speed up thecharacterisation of novel gene functions as well as indicating 

non-essential genes and/or regions in the human genome. Finally, I proposed designing a single 

nucleotide variant (SNV) array with probes for all possible stop-gains (nonsense variants) in the 

human genome (n≈ 4.5 million)and using it to screen highly consanguineous populations with a rich 

gene pool (e.g. the population of Riyadh) to make the process more efficient. 

Knockout studies in model organisms are well established and have hugely facilitated our 

understanding of our own genome and the biological pathways which connect many of the twenty 

thousand or so genes. However, where not backed up by human observational studies, animal knock-

outs can be misleading as the underlying mechanism may be different in the model organism or the 

gene may have a different (or other acquired) function(s). Also some human genes lack homologues in 

the commonly analysed model organisms (some may even have no homologues, also known as 

‘orphan’ genes) which is another limitation of these gene knockout studies. Therefore candidate genes 

derived from model organism ‘knockouts’ cannot be directly translated to a human model until the 

same phenotype is also observed in humans. However, sampling randomly from a consanguineous 

population will enable the identification of natural human knock-outs, enabling the identification of 

house-keeping genes (i.e. when knocked out, are lethal before reaching puberty), non-essential genes 

(i.e. when knocked out, do not cause any clinical outcomes early or late in life), genes which cause late 

onset disorders (e.g. highly penetrant mutations in certain genes causing certain cancers) and genes 

causing embryo loss - alongside the Mendelian (and monogenic forms of common) disease causal 

ones. In this sense, studies of consanguineous populations can be used as examples of a ‘quasi-reverse 

genetics’ study (QRG), with direction of study being ‘genotype to phenotype’, similar to the reverse 

genetics studies carried out in model organisms. To put simply, which genes have been inactivated in a 

consanguineous individual can be determined initially using whole-exome sequencing (WES) or 

genotyping, then the short-term and long-term effects of the knockouts can be observed; if any.  

Ultimately, findings from ‘complete knock-outs’ can have considerable implications at the 

‘population’ level, and not just for the respective families/individuals (e.g. by facilitating useful drug 

target identification, elucidating underlying biology of certain traits/diseases). 

 

 

IV INTERNATIONAL SCIENTIFIC CONFERENCE OF YOUNG RESEARCHERS 

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Qafqaz University                                                                                          29-30 April 2016, Baku, Azerbaijan 

 

 

 

PROCEEDINGS 

SECTION I 

NATURAL SCIENCES 

 

Physics

Mathematics

Chemistry and Chemical Engineering 

Biology

 

 

 

IV INTERNATIONAL SCIENTIFIC CONFERENCE OF YOUNG RESEARCHERS 

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Qafqaz University                                                                                          29-30 April 2016, Baku, Azerbaijan 

 

 

 

 

 

 

 

 

 

 

 

 

 

IV INTERNATIONAL SCIENTIFIC CONFERENCE OF YOUNG RESEARCHERS 

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Qafqaz University                                                                                          29-30 April 2016, Baku, Azerbaijan 

 

 

 

 

PROCEEDINGS 

SECTION I 

NATURAL SCIENCES 

 

 

Physics 

 

 

 

 

 

IV INTERNATIONAL SCIENTIFIC CONFERENCE OF YOUNG RESEARCHERS 

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Qafqaz University                                                                                          29-30 April 2016, Baku, Azerbaijan 

EXPERIMENTAL DATA INTERPRETATION FOR MOLECULAR 

MODELING OF THE PROTEIN–DNA COMPLEXES STRUCTURE 

 

G.A. ARMEEV, A.K. SHAYTAN 

Lomonosov Moscow State University   

[e-mail] 

RUSSIA 

 

DNA is a linear molecule that carries most of the genetic information of organism. There are 

several levels of DNA organisation since the eukaryotic genome in its fully unfolded form cannot fit 

into a relatively compact nucleus. DNA storage and fine regulation of the cell genetic apparatus is 

carried out at the level of individual nucleosomes. The structure of nucleosomes affects a number of 

processes, such as DNA transcription, replication, and repair. Nucleosome structure is determined with 

nearly atomic resolution by X-ray diffraction however it is difficult to study the higher levels of 

chromatin organization by the usual methods of structural biology. In this account we discuss the 

question of constructing three-dimensional models of DNA in complex with proteins using computer 

modeling and indirect methods of studying the conformation of macromolecules. We discuss some 

aspects of integrating such data into the process of constructing the molecular models of protein-DNA 

complexes based on the geometric characteristics of DNA. We propose an algorithm for estimating 

conformations of protein-DNA complexes based on the information about the local flexibility of DNA 

and on the experimental data obtained by Forster resonance energy transfer (FRET) and hydroxyl 

footprinting. Finally, we use this algorithm to predict the hypothetical configuration of DNA in a 

nucleosome bound with histone H1.  

To date, the nucleosome-H1 complex is not in the PDB data bank of three-dimensional protein 

structures. However, the works in which the structure of this complex has been studied by nuclear 

magnetic resonance are available. Histone H1, also known as the linker histone, forms a complex with 

nucleo-somes that promotes a higher level of the DNA compaction. Providing such an impact on the 

arrangement/ordering of DNA in the cell, histone H1 plays an important role in the regulation of gene 

expression. Structural features of the interactions between the linker histone and nucleosome are still 

unknown and their studies attract great interest. 

To construct the model, we used the structure 1KX5 from the PDB data bank as the basis; linkers 

were added to this structure in accordance with the sequence used in the FRET experiment. Based on 

the footprinting data, we selected the DNA segments that are not bound to protein. After minimizing 

the DNA geometry using the distance constraints obtained from the FRET data, an asymmetric 

structure with a parallel arrangement of the DNA linker segments was obtained (Fig. 1). Very similar 

models were obtained in, where the structure of chromatosomes was studied by hydroxyl footprinting 

and electron microscopy. In the future, the resulting structure can be used as a target for the 

macromolecular docking of histone H1. 

The developed method makes it possible to create the geometry models of DNA in complex with 

proteins using the molecular modeling based on the integration of the experimental data and the data 

on the local rigidity of DNA. This method also enables us to obtain atomistic models and to study the 

structural characteristics of single nucleosomes and their complexes with other macromolecules. Using 

the example of a chromatosome, we demonstrate the fundamental possibility to obtain the geometry of 

the linker DNA, which is important for the understanding the chromatin organization. 

Acknowledgement 

We thank M.P. Kirpichnikov, V.M. Studitskii, A.V. Feofanov, and the members of their 

laboratories for providing the experimental data 

Development of nucleosome visualization algorithms was supported by Russian Science 

Foundation (grant No. 14-24-00031). A.S. was supported by the US–Russia Collaboration in the 

Biomedical Sciences National Institutes of Health visiting fellows' program. 

 

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IV INTERNATIONAL SCIENTIFIC CONFERENCE OF YOUNG RESEARCHERS 

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Qafqaz University                                                                                          29-30 April 2016, Baku, Azerbaijan 

Another application of the WRF-Chem model is to understand high wintertime ozone pollution 

events over the Uinta Basin, Utah. The basin is densely populated by thousands of oil and natural gas 

wells. Our air quality simulations were able to reproduce the observed multi-day buildup of 

atmospheric pollutants and accompanying rapid photochemical ozone formation in the Uinta Basin. 

The model results demonstrate that very high emissions of volatile organic compounds associated with 

oil and natural gas production, storage and processing contribute significantly to high ozone formation 

over the in the Uinta Basin. Shallow boundary layers and snow cover are also key factors driving the 

high ozone events in winter. 

The state of the art WRF-Chem air quality model presented here may help to address the 

emerging science and policy related questions related to air pollution over urban and industrial regions 

across the globe.