Target Information

Target General Information

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Target ID

T35799 (Former ID: TTDI02598)

Target Name

DNA mismatch repair protein Mlh1 (MLH1)

Synonyms

MutL protein homolog 1; COCA2

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Gene Name

MLH1

Target Type

Literature-reported target

[1]

Function

DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis. Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR).

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UniProt ID

MLH1_HUMAN

Sequence

MSFVAGVIRRLDETVVNRIAAGEVIQRPANAIKEMIENCLDAKSTSIQVIVKEGGLKLIQ
IQDNGTGIRKEDLDIVCERFTTSKLQSFEDLASISTYGFRGEALASISHVAHVTITTKTA
DGKCAYRASYSDGKLKAPPKPCAGNQGTQITVEDLFYNIATRRKALKNPSEEYGKILEVV
GRYSVHNAGISFSVKKQGETVADVRTLPNASTVDNIRSIFGNAVSRELIEIGCEDKTLAF
KMNGYISNANYSVKKCIFLLFINHRLVESTSLRKAIETVYAAYLPKNTHPFLYLSLEISP
QNVDVNVHPTKHEVHFLHEESILERVQQHIESKLLGSNSSRMYFTQTLLPGLAGPSGEMV
KSTTSLTSSSTSGSSDKVYAHQMVRTDSREQKLDAFLQPLSKPLSSQPQAIVTEDKTDIS
SGRARQQDEEMLELPAPAEVAAKNQSLEGDTTKGTSEMSEKRGPTSSNPRKRHREDSDVE
MVEDDSRKEMTAACTPRRRIINLTSVLSLQEEINEQGHEVLREMLHNHSFVGCVNPQWAL
AQHQTKLYLLNTTKLSEELFYQILIYDFANFGVLRLSEPAPLFDLAMLALDSPESGWTEE
DGPKEGLAEYIVEFLKKKAEMLADYFSLEIDEEGNLIGLPLLIDNYVPPLEGLPIFILRL
ATEVNWDEEKECFESLSKECAMFYSIRKQYISEESTLSGQQSEVPGSIPNSWKWTVEHIV
YKALRSHILPPKHFTEDGNILQLANLPDLYKVFERC

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3D Structure

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AlphaFold

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: adenosine diphosphate

Ligand Info

Structure Description

Crystal Structure of human MLH1

PDB:4P7A

Method

X-ray diffraction

Resolution

2.30 Å

Mutation

[2]

PDB Sequence

FVAGVIRRLD

¹²

ETVVNRIAAG

²²

EVIQRPANAI

³²

KEMIENCLDA

⁴²

KSTSIQVIVK

⁵²

EGGLKLIQIQ

⁶²

DNGTGIRKED

⁷²

LDIVCERFTT

⁸²

SKLGFRGEAL

¹⁰⁴

ASISHVAHVT

¹¹⁴

ITTKTADGKC

¹²⁴

AYRASYSDGK

¹³⁴

LKAPPKPCAG

¹⁴⁴

NQGTQITVED

¹⁵⁴

LFYNIATRRK

¹⁶⁴

ALKNPSEEYG

¹⁷⁴

KILEVVGRYS

¹⁸⁴

VHNAGISFSV

¹⁹⁴

KKQGETVADV

²⁰⁴

RTLPNASTVD

²¹⁴

NIRSIFGNAV

²²⁴

SRELIEIGCE

²³⁴

DKTLAFKMNG

²⁴⁴

YISNANYSVK

²⁵⁴

KCIFLLFINH

²⁶⁴

RLVESTSLRK

²⁷⁴

AIETVYAAYL

²⁸⁴

PKNTHPFLYL

²⁹⁴

SLEISPESIL

³²³

ERVQQHIESK

³³³

LLG

Residue

Distance (Å)

MET35

4.881

ASN38

3.053

CYS39

3.991

ASP41

4.592

ALA42

3.347

ASP63

2.923

THR66

4.682

GLY67

3.576

ILE68

3.391

VAL76

3.237

THR81

3.605

THR82

2.536

Residue

Distance (Å)

SER83

2.584

LYS84

2.784

PHE99

4.820

ARG100

3.408

GLY101

2.901

GLU102

3.985

ALA103

3.413

LEU104

2.915

ALA105

4.437

THR148

3.614

ILE150

4.589

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Mismatch repair	hsa03430	Affiliated Target
Class: Genetic Information Processing => Replication and repair	Pathway Hierarchy
Fanconi anemia pathway	hsa03460	Affiliated Target
Class: Genetic Information Processing => Replication and repair	Pathway Hierarchy

Degree	19	Degree centrality	2.04E-03	Betweenness centrality	7.88E-04
Closeness centrality	2.34E-01	Radiality	1.41E+01	Clustering coefficient	3.45E-01
Neighborhood connectivity	4.25E+01	Topological coefficient	1.02E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

References

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REF 1

DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells. Oncotarget. 2014 Nov 30;5(22):11297-307.

REF 2

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71(Pt 8):981-5.

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