4DPG

Crystal Structure of Human LysRS: P38/AIMP2 Complex I

External Resource: Annotation

Domain Annotation: SCOP/SCOPe Classification
Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations

Domain Annotation: SCOP/SCOPe Classification SCOP-e Database Homepage

Chains	Domain Info	Class	Fold	Superfamily	Family	Domain	Species	Provenance Source (Version)
A	d4dpga1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
A	d4dpga2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
B	d4dpgb1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
B	d4dpgb2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
D	d4dpgd1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
D	d4dpgd2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
E	d4dpge1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
E	d4dpge2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
F	d4dpgf1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
F	d4dpgf2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
G	d4dpgg1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
G	d4dpgg2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
H	d4dpgh1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
H	d4dpgh2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
C	d4dpgc1	All beta proteins	OB-fold	Nucleic acid-binding proteins	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
C	d4dpgc2	Alpha and beta proteins (a+b)	Class II aaRS and biotin synthetases	Class II aaRS and biotin synthetases	automated matches	automated matches	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
I	SCOP2B Superfamily	AIMP2 lysyl-tRNA synthetase binding domain-like	8092962	3002650	SCOP2B (2022-06-29)
J	SCOP2B Superfamily	AIMP2 lysyl-tRNA synthetase binding domain-like	8092962	3002650	SCOP2B (2022-06-29)
K	SCOP2B Superfamily	AIMP2 lysyl-tRNA synthetase binding domain-like	8092962	3002650	SCOP2B (2022-06-29)
L	SCOP2B Superfamily	AIMP2 lysyl-tRNA synthetase binding domain-like	8092962	3002650	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
A	tRNA_anti-codon	e4dpgA4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
A	tRNA-synt_2	e4dpgA3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)
B	tRNA_anti-codon	e4dpgB4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
B	tRNA-synt_2	e4dpgB3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)
D	tRNA_anti-codon	e4dpgD4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
D	tRNA-synt_2	e4dpgD3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)
E	tRNA_anti-codon	e4dpgE4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
E	tRNA-synt_2	e4dpgE3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)
F	tRNA_anti-codon	e4dpgF4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
F	tRNA-synt_2	e4dpgF3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)
G	tRNA_anti-codon	e4dpgG4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
G	tRNA-synt_2	e4dpgG3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)
H	tRNA_anti-codon	e4dpgH4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
H	tRNA-synt_2	e4dpgH3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)
C	tRNA_anti-codon	e4dpgC4	A: beta barrels	X: OB-fold	H: Nucleic acid-binding proteins (From Topology)	T: Nucleic acid-binding proteins	F: tRNA_anti-codon	ECOD (1.6)
C	tRNA-synt_2	e4dpgC3	A: a+b three layers	X: Class II aaRS and biotin synthetases (From Topology)	H: Class II aaRS and biotin synthetases (From Topology)	T: Class II aaRS and biotin synthetases	F: tRNA-synt_2	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
A	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)
B	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
B	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)
D	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
D	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)
E	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
E	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)
F	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
F	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)
G	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
G	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)
H	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
H	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)
C	2.40.50.140	Mainly Beta	Beta Barrel	OB fold (Dihydrolipoamide Acetyltransferase, E2P)	Nucleic acid-binding proteins	CATH (4.3.0)
C	3.30.930.10	Alpha Beta	2-Layer Sandwich	BirA Bifunctional Protein	domain 2	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, B, C, D, E A, B, C, D, E, F, G, H	PF00152	tRNA synthetases class II (D, K and N) (tRNA-synt_2)	tRNA synthetases class II (D, K and N)	-	Domain
A, B, C, D, E A, B, C, D, E, F, G, H	PF01336	OB-fold nucleic acid binding domain (tRNA_anti-codon)	OB-fold nucleic acid binding domain	This family contains OB-fold domains that bind to nucleic acids [4]. The family includes the anti-codon binding domain of lysyl, aspartyl, and asparaginyl -tRNA synthetases (See Pfam:PF00152). Aminoacyl-tRNA synthetases catalyse the addition of an a ...	This family contains OB-fold domains that bind to nucleic acids [4]. The family includes the anti-codon binding domain of lysyl, aspartyl, and asparaginyl -tRNA synthetases (See Pfam:PF00152). Aminoacyl-tRNA synthetases catalyse the addition of an amino acid to the appropriate tRNA molecule EC:6.1.1.-. This family also includes part of RecG helicase involved in DNA repair. Replication factor A is a hetero-trimeric complex, that contains a subunit in this family [2,3]. This domain is also found at the C-terminus of bacterial DNA polymerase III alpha chain.	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, B, C, D, E A, B, C, D, E, F, G, H	Lysine--tRNA ligase	ligase activity, forming carbon-oxygen bonds aminoacyl-tRNA ligase activity catalytic activity, acting on RNA catalytic activity, acting on a nucleic acid catalytic activity, acting on a tRNA lysine-tRNA ligase activity catalytic activity ligase activity ATP:ADP adenylyltransferase activity adenylyltransferase activity transferase activity nucleotidyltransferase activity transferase activity, transferring phosphorus-containing groups binding ligase activity, forming carbon-oxygen bonds aminoacyl-tRNA ligase activity catalytic activity, acting on RNA catalytic activity, acting on a nucleic acid catalytic activity, acting on a tRNA lysine-tRNA ligase activity catalytic activity ligase activity ATP:ADP adenylyltransferase activity adenylyltransferase activity transferase activity nucleotidyltransferase activity transferase activity, transferring phosphorus-containing groups binding amino acid binding RNA binding organic cyclic compound binding tRNA binding nucleic acid binding adenyl ribonucleotide binding nucleotide binding purine ribonucleotide binding purine ribonucleoside triphosphate binding nucleoside phosphate binding ion binding purine nucleotide binding anion binding adenyl nucleotide binding ATP binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding small molecule binding identical protein binding protein binding protein homodimerization activity protein dimerization activity	nucleoside phosphate metabolic process nucleotide biosynthetic process primary metabolic process diadenosine polyphosphate metabolic process nucleobase-containing compound biosynthetic process nucleotide metabolic process diadenosine polyphosphate biosynthetic process nucleobase-containing compound metabolic process diadenosine tetraphosphate metabolic process biosynthetic process organophosphate metabolic process organophosphate biosynthetic process nucleobase-containing small molecule metabolic process nucleoside phosphate biosynthetic process phosphate-containing compound metabolic process nucleoside phosphate metabolic process nucleotide biosynthetic process primary metabolic process diadenosine polyphosphate metabolic process nucleobase-containing compound biosynthetic process nucleotide metabolic process diadenosine polyphosphate biosynthetic process nucleobase-containing compound metabolic process diadenosine tetraphosphate metabolic process biosynthetic process organophosphate metabolic process organophosphate biosynthetic process nucleobase-containing small molecule metabolic process nucleoside phosphate biosynthetic process phosphate-containing compound metabolic process metabolic process cellular process small molecule metabolic process phosphorus metabolic process diadenosine tetraphosphate biosynthetic process regulation of macrophage activation multicellular organismal process regulation of biological process positive regulation of macrophage activation regulation of cellular process regulation of leukocyte activation cell activation biological regulation positive regulation of biological process regulation of cell activation myeloid leukocyte activation leukocyte activation macrophage activation positive regulation of cell activation immune system process positive regulation of leukocyte activation positive regulation of multicellular organismal process regulation of multicellular organismal process regulation of immune system process positive regulation of immune system process positive regulation of cellular process cellular response to stimulus response to stimulus signaling intracellular signal transduction cell communication intracellular signaling cassette MAPK cascade ERK1 and ERK2 cascade signal transduction response to X-ray response to ionizing radiation response to radiation response to abiotic stimulus RNA metabolic process gene expression macromolecule biosynthetic process nucleic acid metabolic process tRNA metabolic process RNA biosynthetic process nucleic acid biosynthetic process tRNA processing macromolecule metabolic process RNA processing basophil activation involved in immune response immune response cell activation involved in immune response myeloid cell activation involved in immune response immune effector process basophil activation leukocyte activation involved in immune response granulocyte activation positive regulation of DNA-templated transcription positive regulation of macromolecule biosynthetic process regulation of primary metabolic process positive regulation of metabolic process DNA-templated transcription regulation of RNA metabolic process positive regulation of biosynthetic process positive regulation of macromolecule metabolic process regulation of nucleobase-containing compound metabolic process regulation of RNA biosynthetic process regulation of biosynthetic process positive regulation of nucleobase-containing compound metabolic process regulation of macromolecule metabolic process positive regulation of RNA metabolic process regulation of gene expression positive regulation of RNA biosynthetic process regulation of macromolecule biosynthetic process regulation of DNA-templated transcription regulation of metabolic process regulation of defense response regulation of response to external stimulus inflammatory response to antigenic stimulus positive regulation of response to stimulus positive regulation of response to external stimulus positive regulation of inflammatory response positive regulation of immune response response to stress regulation of response to stress defense response regulation of inflammatory response to antigenic stimulus response to external stimulus regulation of inflammatory response positive regulation of inflammatory response to antigenic stimulus regulation of response to stimulus positive regulation of defense response regulation of immune response inflammatory response lysyl-tRNA aminoacylation amino acid activation tRNA aminoacylation amino acid metabolic process translation tRNA aminoacylation for protein translation protein metabolic process	membrane-bounded organelle intracellular organelle cellular anatomical structure intracellular anatomical structure mitochondrion organelle cytoplasm intracellular membrane-bounded organelle cytosol cell periphery plasma membrane membrane nucleus membrane-enclosed lumen membrane-bounded organelle intracellular organelle cellular anatomical structure intracellular anatomical structure mitochondrion organelle cytoplasm intracellular membrane-bounded organelle cytosol cell periphery plasma membrane membrane nucleus membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen nuclear lumen protein-containing complex catalytic complex aminoacyl-tRNA synthetase multienzyme complex intracellular protein-containing complex extracellular region extracellular space mitochondrial matrix
I, J, K, L	Aminoacyl tRNA synthase complex-interacting multifunctional protein 2	molecular adaptor activity	cellular component organization cellular component biogenesis cellular component assembly protein-containing complex organization protein-containing complex assembly cellular process cellular component organization or biogenesis developmental process multicellular organismal process epithelium development cellular developmental process tube development animal organ development respiratory tube development cellular component organization cellular component biogenesis cellular component assembly protein-containing complex organization protein-containing complex assembly cellular process cellular component organization or biogenesis developmental process multicellular organismal process epithelium development cellular developmental process tube development animal organ development respiratory tube development lung epithelium development tissue development type II pneumocyte differentiation epithelial cell differentiation lung secretory cell differentiation lung epithelial cell differentiation multicellular organism development lung cell differentiation cell differentiation anatomical structure development lung development respiratory system development system development negative regulation of cell population proliferation regulation of biological process cell population proliferation regulation of cellular process regulation of cell population proliferation negative regulation of cellular process biological regulation negative regulation of biological process apoptotic process cell death programmed cell death regulation of protein modification process positive regulation of protein metabolic process positive regulation of biological process regulation of protein ubiquitination positive regulation of post-translational protein modification regulation of primary metabolic process positive regulation of metabolic process positive regulation of protein modification process protein ubiquitination positive regulation of macromolecule metabolic process protein metabolic process regulation of protein modification by small protein conjugation or removal protein modification process positive regulation of cellular process positive regulation of protein modification by small protein conjugation or removal positive regulation of protein ubiquitination regulation of post-translational protein modification regulation of protein metabolic process primary metabolic process regulation of macromolecule metabolic process macromolecule modification metabolic process macromolecule metabolic process post-translational protein modification regulation of metabolic process protein modification by small protein conjugation protein modification by small protein conjugation or removal biosynthetic process translation gene expression macromolecule biosynthetic process	cellular anatomical structure membrane protein-containing complex catalytic complex aminoacyl-tRNA synthetase multienzyme complex intracellular protein-containing complex intracellular anatomical structure cytoplasm cytosol membrane-bounded organelle intracellular organelle organelle nucleus intracellular membrane-bounded organelle

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, B, C, D, E A, B, C, D, E, F, G, H	IPR045864	Class II Aminoacyl-tRNA synthetase/Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL)	Homologous Superfamily
A, B, C, D, E A, B, C, D, E, F, G, H	IPR034762	Bacterial/eukaryotic lysine-tRNA ligase, class II	Family
A, B, C, D, E A, B, C, D, E, F, G, H	IPR006195	Aminoacyl-tRNA synthetase, class II	Domain
A, B, C, D, E A, B, C, D, E, F, G, H	IPR002313	Lysine-tRNA ligase, class II	Family
A, B, C, D, E A, B, C, D, E, F, G, H	IPR044136	Lysine-tRNA ligase, class II, N-terminal	Domain
A, B, C, D, E A, B, C, D, E, F, G, H	IPR004365	OB-fold nucleic acid binding domain, AA-tRNA synthetase-type	Domain
A, B, C, D, E A, B, C, D, E, F, G, H	IPR018149	Lysyl-tRNA synthetase, class II, C-terminal	Domain
A, B, C, D, E A, B, C, D, E, F, G, H	IPR012340	Nucleic acid-binding, OB-fold	Homologous Superfamily
A, B, C, D, E A, B, C, D, E, F, G, H	IPR004364	Aminoacyl-tRNA synthetase, class II (D/K/N)	Domain
I, J, K, L	IPR031889	AIMP2, lysyl-tRNA synthetase binding domain	Domain
I, J, K, L	IPR004046	Glutathione S-transferase, C-terminal	Domain
I, J, K, L	IPR042360	Aminoacyl tRNA synthase complex-interacting multifunctional protein 2	Family
I, J, K, L	IPR041503	AIMP2, thioredoxin-like domain	Domain
I, J, K, L	IPR036282	Glutathione S-transferase, C-terminal domain superfamily	Homologous Superfamily

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A, B, C, D, E A, B, C, D, E, F, G, H	Pharos: Q15046	autosomal recessive nonsyndromic deafness 89 Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease recessive intermediate B nonsyndromic genetic deafness peripheral neuropathy psoriasis acute myeloid leukemia dermatomyositis large cell medulloblastoma MALT lymphoma motor peripheral neuropathy ovarian cancer plasma cell myeloma astrocytic tumor diabetes mellitus autosomal recessive nonsyndromic deafness 89 Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease recessive intermediate B nonsyndromic genetic deafness peripheral neuropathy psoriasis acute myeloid leukemia dermatomyositis large cell medulloblastoma MALT lymphoma motor peripheral neuropathy ovarian cancer plasma cell myeloma astrocytic tumor diabetes mellitus lung cancer medulloblastoma neurodegenerative disease peripheral nervous system disease primary cutaneous T-cell non-Hodgkin lymphoma attention deficit hyperactivity disorder, inattentive type intellectual disability lymphoplasmacytic lymphoma Mitochondrial Diseases
I, J, K, L	Pharos: Q13155	astrocytic tumor leukodystrophy lung cancer ovarian cancer glioblastoma leukodystrophy, hypomyelinating, 17 malignant glioma Sjogren syndrome large cell medulloblastoma lung adenocarcinoma medulloblastoma

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729.