Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B
Our previous work on the classification of binding site conformations of protein tyrosine phosphatase 1B was published in 2012. It was then found that 102 active sites from 91 PDB files can be divided into 5 major clusters. Since that time, the number of the enzyme PDB files, which are deposited in...
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Ukrainica Bioorganica Acta| _version_ | 1871193610105389056 |
|---|---|
| author | Tanchuk, Vsevolod Y. Kobzar, Olexandr L. Vovk, Andriy I. |
| author_facet | Tanchuk, Vsevolod Y. Kobzar, Olexandr L. Vovk, Andriy I. |
| author_institution_txt_mv | [
{
"author": "Vsevolod Y. Tanchuk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Olexandr L. Kobzar",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Andriy I. Vovk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Tanchuk, Vsevolod Y. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | Our previous work on the classification of binding site conformations of protein tyrosine phosphatase 1B was published in 2012. It was then found that 102 active sites from 91 PDB files can be divided into 5 major clusters. Since that time, the number of the enzyme PDB files, which are deposited in the RCSB Protein Data Bank, and the number of PTP1B crystal structures in these files have been quadrupled emphasizing the importance of this enzyme as a target for drug design. In the present paper, 793 binding sites from 374 PDB files of PTP1B available now were analyzed. Although the clustering results seem to have remained the same since the first investigation, some centroids have been changed and the number of structures in the clusters has increased. Clusters with closed WPD loops, except one, retained their centroids. Most new conformations with open WPD-loop appear in one cluster, which includes crystal structures where ligands occupy the catalytic pockets or are located at the enzyme allosteric sites. The updated clusters can be used for molecular docking-based designing inhibitors of PTP1B  |
| doi_str_mv | 10.15407/bioorganica2024.01.052 |
| first_indexed | 2025-07-17T12:20:01Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
UDC 577.152.3
DOI: https://doi.org/10.15407/bioorganica2024.01.052
52
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
Classification of active site conformations of protein tyrosine
phosphatase 1B revisited
Vsevolod Y. Tanchuk*, Oleksandr L. Kobzar, Andriy I. Vovk
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: Our previous work on the classification of binding site conformations of protein tyrosine phosphatase 1B was published in
2012. It was then found that 102 active sites from 91 PDB files can be divided into 5 major clusters. Since that time, the number of the
enzyme PDB files, which are deposited in the RCSB Protein Data Bank, and the number of PTP1B crystal structures in these files have
been quadrupled emphasizing the importance of this enzyme as a target for drug design. In the present paper, 793 binding sites from
374 PDB files of PTP1B available now were analyzed. Although the clustering results seem to have remained the same since the first
investigation, some centroids have been changed and the number of structures in the clusters has increased. Clusters with closed WPD
loops, except one, retained their centroids. Most new conformations with open WPD-loop appear in one cluster, which includes crystal
structures where ligands occupy the catalytic pockets or are located at the enzyme allosteric sites. The updated clusters can be used for
molecular docking-based designing inhibitors of PTP1B.
Keywords: PTP1B; active sites; conformations; clustering; structure similarity.
Introduction
Protein tyrosine phosphatase 1B (PTP1B) catalyzing the
dephosphorylation of phosphotyrosine residues in proteins
plays important roles in cellular functions and pathogenesis
[1, 2]. This enzyme is one of the therapeutic targets for the
treatment of type 2 diabetes, obesity, cancer, and other
diseases [3, 4]. Despite the considerable interest in the
development of PTP1B inhibitors, none of the compounds
effectively targeting this enzyme have yet passed clinical
trials [5-7]. For designing the new inhibitors of PTP1B,
molecular docking in combination with other computational
approaches is used [8-10]. Many X-ray crystal structures of
PTP1B from the RCSB Protein Data Bank
(https://www.rcsb.org) [11] can be downloaded to evaluate
the ligand-protein binding affinity. However, the methods
Received:
Revised:
Accepted:
Published online:
17.03.2024
28.04.2024
18.05.2024
30.06.2024
Corresponding author. Tel.: +380-44-558-5388;
e-mail: v_tanchuk@yahoo.com (V.Y. Tanchuk)
ORCID: 0000-0001-9055-870X
of rigid molecular docking treat the PTP1B as a rigid
structure, hence the differences in the conformation of the
WPD loop and some amino acid residues can affect the
docking scores. Other methods such as molecular dynamic
simulation or flexible molecular docking require significant
computational resources and more time.
Our previous work on the classification of binding site
conformations of protein tyrosine phosphatase 1B was
published in 2012 [12]. The structures available in the
RCSB Protein data bank at the time of publication were
analyzed and clustered using a special software tool [13]
created for such studies. The number of structures in the
RCSB Protein Data Bank has currently almost tripled
increasing from around 75,000 in 2011 to 222,000 today,
and the number of PDB files containing PTP1B crystal
structures has been quadrupled. Therefore, the goal of this
article is to cluster and analyze the PTP1B structures
available in 2024 and compare the obtained results with the
previous data.
Results and Discussion
ACTPDBCMP is a clustering tool [12, 13], that can read
files in PDB format, align the pairs of proteins having
overlapped tertiary structures, and evaluate the
© Tanchuk V.Y. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
V.Y. Tanchuk, O.L. Kobzar et al.
53
conformational deviation of separate amino acid residues.
In the case of PTP1B, the residues of both catalytic and
some other ligand binding sites were selected as a template
for analyzing them in all other files. For example, the
crystal of 1Q6T [14] contains the aryldifluoromethyl-
phosphonate inhibitor covering the catalytic and secondary
binding sites. The residues of the WPD loop [15] and the
residues up to 5 Å away from the ligand molecule form the
resulting fragment consisting of 32 amino acid residues for
further structural analysis.
In the previous report [12] we analyzed 102 binding sites
from 91 PDB files of PTP1B which were available in 2011.
All PTP1B structures were divided into five main clusters
with two additional clusters for ligand-free and mutated
enzymes (Table 1).
In 2024, the search on the Protein Data Bank server with
the keyword “PTP1B” gave 374 PDB files. Some old files
were no longer available in PDB format, but they remain
available in the newer CIF format. In general, the total
number of PDB files of PTP1B crystallized structures,
including old files, reached 399 increasing by almost 300%
since 2011. This reveals that PTP1B is an important
therapeutic target for searching for new inhibitors that
might be useful in drug discovery.
Today, the total number of active sites in the PDB files
was 793. The sites were not found in 63 files due to the
amino acid mutations. The 793 active sites from 336 PDB
files were clustered by a new version of ACTPDBCMP
Table 1. Clustering of PDB structures [12] and the centroid bound ligands.
Cluster
Centroid
(PDB code)
Number of
structures
RMSD from ligand-
free 2HNP (Å) WPD-loop
Cocrystallized
ligand*
1 2HNP 1 - Open (ligand-free) -
2 1OEM 2 2.84 Open (oxidized Cys215) -
3 1NL9 7 1.37 Open 1
4 1PH0 15 1.02 Open 2
5 2CNF 22 2.39 Closed 3
6 1Q6M 11 2.51 Closed 4
7 2CM8 44 2.23 Closed 5
*The ligands 1-5 formulas are presented in Figure 1.
Figure 1. Formulas of ligands bound to centroids: 1 (1NL9) – in the active site [16]; 2 (1PH0) – in the active site [17]; 3 (2CNF) – in the
active site [18]; 4 (1Q6M) – in the active site [14]; 5 (2CM8) – in the active site [19]; 6 (5QFR) – not in the active site [20]; 7 (7KLX) –
not in the active site [21]; 8 (5QFZ) – not in the active site [20]; 9 (2FJM) –in the active site [22].
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
54
Table 2. Summary of new clustering of PDB structures.
Cluster
Centroid
(PDB code)
Number of
structures
Chain Conformation
Old
centroid
RMSD WPD-loop
Cocrystallized
ligand*
1 2HNP 1 A 2HNP - Open -
2 3A5K 1 A 2HNP 2.21 Open -
3 4QAH 1 A 2HNP 1.18 Open TSR
4 4QAP 1 A A 2HNP 1.28 Open TSR
5 7MOV 1 B B 2HNP 1.00 Open TSR
6 5QFR 4 A C 2HNP 0.99 Open 6
7 7KLX 7 A B 1OEM 1.66 Open 7
8 7KEY 43 A 1NL9 0.74 Open Acetate
9 5QFZ 590 A A 1PH0 1.00 Open 8
10 2FJM 15 A B 1Q6M 2.37 Closed 9
11 2CNF 33 2CNF 2.39 Closed 3
12 2CM8 96 2CM8 2.23 Closed 5
*The ligands 3, 5, 6-9 formulas are presented in Figure 1.
Figure 2. Aligned amino acid residues of the active sites of PTP1B with PDB code 1PH0 (yellow) and 5QFZ (red).
[13], which was created for the classification of PTP1B
structures. Compared to its old version used in the previous
report [12], the program can handle much larger volumes of
data and takes into account alternative conformations of
amino acid residues. A summary of new clustering is
presented in Table 2.
As can be seen, the number of clusters increased to 12,
but some new clusters are represented by individual
structures with peculiarities. For example, centroid 3A5K is
ligand-free, but has a Mg2+ ion which is located near
Glu130. This centroid also has a mutation of Cys121 to
Trp121, therefore the conformation of Lys120 is very
different from the one in the case of 2HNP. The structures
with PDB codes 4QAH and 4QAP, in which Thr263 was
replaced by Lys263 or Asn263, respectively, contain only
the tris(hydroxymethyl)aminomethane (TRS) molecule
somewhere near the Glu130 [23]. The crystal 7MOV from
[24] is an example of the classification when four
conformations available in this PDB file are distributed
between three clusters. Conformation B of chain B forms a
separate cluster. Conformation B of chain A belongs to
cluster 9 with centroid 5QFZ and the rest two
conformations are included in cluster 11 (centroid 2CNF).
Centroid 5QFR represents one of the structures from the
work [20] aimed at the investigation of allosteric sites of
PTP1B. In this crystallized structure, one molecule of
compound 6 binds near Trp16 and Ala17, and another one
near Asp245. Besides that, there is a TSR molecule near
His54.
V.Y. Tanchuk, O.L. Kobzar et al.
55
Table 3. The mobility of amino acid residues in the regions
of the active site and second binding site.
Residue Average
RMSD, Å
Average
RMSD %
Max. RMSD,
Å
PHE182 4.08 100 9.31
ASP181 3.06 74.9 7.5
ARG47 2.22 54.2 8.65
ARG24 1.48 36.3 4.11
ASP48 1.48 36.2 7.86
GLN262 1.47 36 4.23
GLY183 1.32 32.3 5.84
LYS120 1.29 31.6 10.2
ILE219 1.24 30.4 8.39
PRO180 1.24 30.4 3.12
GLY218 1.23 30.2 9.13
TYR46 1.22 29.9 8.2
PRO185 1.16 28.4 6.52
VAL184 0.98 24 4.93
TRP179 0.88 21.5 3.09
THR178 0.79 19.4 2.43
ASP29 0.78 19.2 2.98
ARG221 0.75 18.5 1.91
SER216 0.75 18.4 3.26
ALA217 0.73 17.8 4.34
VAL49 0.7 17.1 3.61
THR177 0.7 17.1 2.06
ARG254 0.65 16 3.79
MET258 0.65 16 2.6
ALA27 0.65 15.9 1.99
PHE30 0.64 15.6 2.12
SER28 0.63 15.5 1.78
CYS215 0.63 15.3 4.76
GLY220 0.61 15 2.61
GLY259 0.61 14.8 2
PHE52 0.6 14.8 1.92
SER222 0.52 12.8 1.56
The remaining clusters are analogues of the old clusters.
Strangely enough, the conformation of 7KLX from [21] is
very similar to oxidized enzyme conformations 1OEM and
1OES from [25] and [26]. These structures and a couple of
other ones form a separate cluster. A new centroid 7KEY
(chain A, conformation A) with three acetic acid molecules
located not in the active site [21] is very similar to the old
centroid 1NL9 containing inhibitor bound in the active site
region [16]. The crystal structure of 5QFZ [20] is a centroid
of the largest cluster including 590 conformations from 214
PDB entries. The old centroid of this cluster was 1PH0 [17],
which contained only 15 structures at the time of our
previous publication. It is interesting to notice that though
1PH0 is a result of designing a selective competitive
inhibitor, and 5QFZ is a result of the investigation of
allosteric effects, both have very similar conformations
(difference of 0.69 Å). In their active sites, large deviations
in the position have been found for Arg47 and Gln262
(Figure 2).
Crystal structure 2FJM [22] with closed WPD-loop
joined to old cluster 1Q6M [14], and its conformation B of
chain A became a centroid. The remaining clusters having
closed WPD-loop have not even changed centroids.
Amino acid residues of clusters 6-12 were sorted by their
mobility. As can be seen from Table 3, the amino acid
residues Phe182 and Asp181 located approximately in the
middle of the WPD-loop have the highest mobility. It
should be noted that the conformational motions of the
WPD-loop in the structure of PTP1B are important in the
catalysis of the dephosphorylation tyrosine residues of the
intracellular signal proteins and some enzymes [27]. The
Asp181 functions as a general acid in the first step and as a
general base catalyst in the second step [28]. The flexibility
of residues Tyr46, Arg47, and Asp48 belonging to the
YRD-loop [29] was significantly increased in comparison
with the movement of P-loop residues such as Cys215,
Arg221, Ser216, Ala217, and Gly220. The side chain of
Lys120 and Q-loop residue Gln262 also underwent
conformational changes. Among the amino acid residues
forming the secondary binding site, except the residue of
Arg24, the lower flexibility was observed for amino acid
residues Phe52, Gly259, Ala27, Met258, and Arg254.
Conclusions
The classification of active site conformations of PTP1B
was revisited after 12 years. Although the number of PDB
files containing PTP1B crystal structures has substantially
increased since 2011, the clusterization results have not
significantly changed. The number of clusters was increased
from 7 to 12. Four of the five new clusters with open WPD-
loop are represented by individual structures having some
peculiarities, and one cluster includes four structures. The
three old clusters with open WPD-loop and one old cluster
with closed WPD-loop changed their centroids. The crystal
structure with PDB code 5QFZ was identified as the
centroid of a large class that includes 590 conformations of
PTP1B. The main types of conformations and determined
centroids can be used for virtual screening by molecular
docking to search for PTP1B inhibitors.
Experimental section
The work was done with the help of a new version of
ACTPDBCMP – a software tool for comparing and
clustering selected parts of protein structures from PDB
files. The new version can deal with much larger volumes
of data, up to 3000 conformations. The software can also
handle alternative conformations often present in PDB files.
The new version is multithreaded and therefore is fast
enough to handle large data sizes. The calculation algorithm
on which the tool is based does a pairwise comparison of
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
56
structures, which means that it is quadratically dependent
on the size of a dataset. As the number of available
structures has drastically increased, the run time becomes
too long. For example, for 700 chains it will be almost 50
times longer than for 100 chains. This can be remedied by
multithreading. Pairwise comparison can be performed in
parallel by multiple threads running on different CPUs. The
number of threads can be defined by the user.
ACTPDBCMP was developed by the authors and is
available at GitHub https://github.com/VTanchukIBOPC/
actpdbcmp.
The list of all PDB entries can be found in:
actpdbcmp/PTP1BLIST.txt at VTanchukIBOPC/actpdbcmp
(github.com).
Notes
Acknowledgments and finances. This work was
supported by the National Academy of Science of Ukraine,
project 0124U001926.
The authors declare no conflict of interest.
Author contributions. V.Y.T.: conceptualization,
software development and updating, clusterization of
crystal structure of the enzyme, and writing of the
manuscript. O.L.K.: formal analysis and writing of the
manuscript. A.I.V.: conceptualization, supervision, and
editing.
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Перегляд класифікації конформацій активного центру
протеїнтирозинфосфатази 1B
В.Ю. Танчук*, О.Л. Кобзар, А.І. Вовк
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Наша попередня робота з класифікації конформацій активних центрів протеїнтирозинфосфатази 1B була опублікована в 2012 році. Т оді
було показано, що 102 активні центри з 91 файлу PDB можна розділити на 5 основних кластерів. З того часу кількість файлів PDB ензиму, які
зберігаються в банку даних RCSB Protein Data Bank, і кількість кристалічних структур PTP1B у цих файлах зросла в чотири рази, що підкреслює
важливість цього ензиму як мішені для розробки ліків. У цій статті проаналізовано 793 центрів зв’язування з 374 PDB-файлів PTP1B, доступних
зараз. Хоча результати кластеризації, здається, залишилися незмінними з часу першого дослідження, деякі центроїди були змінені, а кількість
структур у кластерах зросла. Кластери із закритими WPD-петлями, крім одного, зберегли свої центроїди. Більшість нових конформацій з
відкритою WPD-петлею було віднесено до одного кластеру з кристалічними структурами, де ліганди займають каталітичні центри або
розташовані в алостеричних центрах ензиму. Оновлені кластери можуть бути використані для віртуального скринінгу сполук як інгібіторів
PTP1B.
Ключові слова: PTP1B; активні центри; конформації; кластернізація; структурна подібність.
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| id | oai:ojs2.bioorganica.com.ua:article-84 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:26Z |
| publishDate | 2024 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/7f/f501784574cdf497280cbf61cd0bc67f.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-842026-07-19T14:56:55Z Classification of active site conformations of protein tyrosine phosphatase 1B revisited Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B Tanchuk, Vsevolod Y. Kobzar, Olexandr L. Vovk, Andriy I. PTP1B active sites conformations clustering structure similarity PTP1B активні центри конформації кластернізація структурна подібність Our previous work on the classification of binding site conformations of protein tyrosine phosphatase 1B was published in 2012. It was then found that 102 active sites from 91 PDB files can be divided into 5 major clusters. Since that time, the number of the enzyme PDB files, which are deposited in the RCSB Protein Data Bank, and the number of PTP1B crystal structures in these files have been quadrupled emphasizing the importance of this enzyme as a target for drug design. In the present paper, 793 binding sites from 374 PDB files of PTP1B available now were analyzed. Although the clustering results seem to have remained the same since the first investigation, some centroids have been changed and the number of structures in the clusters has increased. Clusters with closed WPD loops, except one, retained their centroids. Most new conformations with open WPD-loop appear in one cluster, which includes crystal structures where ligands occupy the catalytic pockets or are located at the enzyme allosteric sites. The updated clusters can be used for molecular docking-based designing inhibitors of PTP1B  Наша попередня робота з класифікації конформацій активних центрів протеїнтирозинфосфатази 1B була опублікована в 2012 році. Тоді було показано, що 102 активні центри з 91 файлу PDB можна розділити на 5 основних кластерів. З того часу кількість файлів PDB ензиму, які зберігаються в банку даних RCSB Protein Data Bank, і кількість кристалічних структур PTP1B у цих файлах зросла в чотири рази, що підкреслює важливість цього ензиму як мішені для розробки ліків. У цій статті проаналізовано 793 центрів зв’язування з 374 PDB-файлів PTP1B, доступних зараз. Хоча результати кластеризації, здається, залишилися незмінними з часу першого дослідження, деякі центроїди були змінені, а кількість структур у кластерах зросла. Кластери із закритими WPD-петлями, крім одного, зберегли свої центроїди. Більшість нових конформацій з відкритою WPD-петлею було віднесено до одного кластеру з кристалічними структурами, де ліганди займають каталітичні центри або розташовані в алостеричних центрах ензиму. Оновлені кластери можуть бути використані для віртуального скринінгу сполук як інгібіторів PTP1B  V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2024-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/84 10.15407/bioorganica2024.01.052 Ukrainica Bioorganica Acta; Vol. 19 No. 1 (2024): Ukrainica Bioorganica Acta; 52-57 Ukrainica Bioorganica Acta; Том 19 № 1 (2024): Ukrainica Bioorganica Acta; 52-57 1814-9766 1814-9758 10.15407/bioorganica2024.01 en https://bioorganica.com.ua/index.php/journal/article/view/84/83 Copyright (c) 2024 Vsevolod Y. Tanchuk, Olexandr L. Kobzar, Andriy I. Vovk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | PTP1B активні центри конформації кластернізація структурна подібність Tanchuk, Vsevolod Y. Kobzar, Olexandr L. Vovk, Andriy I. Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B |
| title | Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B |
| title_alt | Classification of active site conformations of protein tyrosine phosphatase 1B revisited |
| title_full | Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B |
| title_fullStr | Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B |
| title_full_unstemmed | Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B |
| title_short | Перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1B |
| title_sort | перегляд класифікації конформацій активного центру протеїнтирозинфосфатази 1b |
| topic | PTP1B активні центри конформації кластернізація структурна подібність |
| topic_facet | PTP1B active sites conformations clustering structure similarity PTP1B активні центри конформації кластернізація структурна подібність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/84 |
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